CAS9 VARIANTS HAVING NON-CANONICAL PAM SPECIFICITIES AND USES

THEREOF RELATED APPLICATIONS

[0001] This application claims priority to U.S. Provisional Patent Application No.62/722,057 filed August 23, 2018, and to U.S. Provisional Patent Application No.62/886,937, filed August 14, 2019, each of which are incorporated herein by reference. BACKGROUND OF THE INVENTION

[0002] CRISPR-Cas systems, and especially systems based on the Cas9 enzyme from

Streptococcus pyogenes (SpCas9) have successfully been engineered for genome editing and base editing in a wide range of organisms. As one example, base editors have been developed that convert Cas endonucleases into programmable nucleotide deaminases ^{1, 2, 3} , thus facilitating the introduction of C-to-T mutations (by C-to-U deamination) or A-to-G mutations (by A-to-I deamination) without induction of a double-strand break ^{4, 5} .

[0003] One drawback of current genome and base engineering tools (e.g., ZNFs, TALENS, and CRISPR/Cas9) is that they are limited with respect to the DNA sequences that can be targeted. For example, ZNF and TALENS are limited because each system requires the design of a specific DNA- binding portion, the amino acid sequence of which being a function of each individual target nucleotide sequence. CRISPR/Cas9 technologies are also limited. While Cas9 can be programmably targeted to virtually any target sequence by providing a suitable guide RNA, Cas9 strictly requires the presence of a protospacer-adjacent motif (PAM)-- which is typically the canonical nucleotide sequence 5¢-NGG-3¢ (e.g., for SpCas9)--immediately adjacent to the 3¢-end of the targeted nucleic acid sequence in order for the Cas9 to bind and act upon the target sequence. This requirement for a PAM sequence effectively limits the nucleotide sequences which can be efficiently targeted by Cas9. [0004] Accordingly, there is a need for nucleic acid programmable DNA binding proteins, such as Cas9, that are capable of binding target nucleotide sequences that lack canonical PAMs(e.g., 5¢-NGG- 3¢ for SpCas9) in order to expand the scope and flexibility of genome and base editing.

SUMMARY OF THE INVENTION

[0005] The clustered regularly interspaced short palindromic repeat (CRISPR) system is a prokaryotic adaptive immune system that has been modified to enable robust genome and nucleobase engineering in a variety of organisms and cell lines. CRISPR-Cas (CRISPR-associated) systems are protein-RNA complexes that use an RNA molecule (sgRNA) as a guide to localize the complex to a target nucleic acid sequence via base-pairing. In the natural systems, a Cas protein then acts as an endonuclease to cleave the targeted DNA sequence. The target nucleic acid sequence must be both complementary to the sgRNA and also contain a“protospacer-adjacent motif”(PAM) at the 3¢-end of the complementary region in order for the system to function. The requirement for a PAM sequence limits the use of Cas9 technology, especially for applications that require precise Cas9 positioning, such as base editing, which requires a PAM approximately 13-17 nucleotides from the target base and some forms of homology-directed repair, which are most efficient when DNA cleavage occurs ~ 10- 20 base pairs away from a desired alteration. To address this limitation, researchers have harnessed natural CRISPR nucleases with different PAM requirements and engineered existing systems to accept variants of naturally recognized PAMs. Other natural CRISPR nucleases shown to function efficiently in mammalian cells include Staphylococcus aureus Cas9 (SaCas9), Acidaminococcus sp. Cpf1 (AsCpf1), Lachnospiraceae bacterium Cpf1, Campylobacter jejuni Cas9, Streptococcus thermophilus Cas9, and Neisseria meningitides Cas9. None of these mammalian cell-compatible CRISPR nucleases, however, offers a PAM that occurs as frequently as that of SpCas9.

[0006] Some aspects of the disclosure relate to novel Cas9 mutants that are capable of binding to target sequences that do not include a canonical PAM sequence (5¢-NGG-3¢, where N is any nucleotide) at the 3¢-end. The disclosure also provides methods of generating and identifying novel Cas9 variants, e.g., using Phage Assisted Continuous Evolution (PACE) and/or Phage Assisted Non- Continuous Evolution (PANCE), that are capable of recognizing (e.g., binding to) target sequences encompassing the a variety of PAM sequences . In particular, methods and compositions have been developed for targeting sequences that have an adenine (A) at the second nucleic acid position of the PAM (e.g., 5¢-NAN-3¢). It should be appreciated that target sequences having PAMs that lack one or more guanines (Gs) are particularly difficult to target given the paucity of SpCas9 activity (e.g., binding activity) on such sequences. One goal of the disclosure is to provide a repertoire of SpCas9 variants that could be selected from for use in genome and/or base editing applications that are specific for a target nucleic acid sequence (e.g., DNA sequence) based on a particular PAM sequence. Such a catalogue/library of SpCas9 variants would be useful for expanding the scope of genome and base editing, so as not to be restricted by any particular PAM requirement. BRIEF DESCRIPTION OF THE DRAWINGS

[0007] Figures 1A-1C show schematic representations of Phage Assisted Continuous Evolution (PACE) of Cas9 and results of SpCas9 vs xCas9 evolution. Figure 1A, PACE takes place in a fixed- volume“lagoon” that is continuously diluted with fresh host E. coli cells. Upon infection, each selection phage (SP) that encodes a Cas9 variant capable of binding the target PAM and protospacer on the accessory plasmid (AP) induces expression of gene III, resulting in infectious progeny phage that propagate the active Cas9 variant in subsequent host cells. Figure 1B, accessory plasmids representing each of 64 PAM sequences are used to select for Cas9 variants capable of binding to the PAM/protospacer sequences, where RNAP fused to the Cas9 variant induces express ion of gene III upon binding to the sequence having the specific PAM. Figure 1C, data (luciferase assay) for overnight phage propagation reveals on which PAMs SpCas9 and xCas9 have binding activity.

xCas9 has a less strict PAM requirement as compared to SpCas9.

[0008] Figures 2A-B show a schematic representation of a Cas964 PAM Phage Assisted Non- Continuous Evolution (PANCE) and results of SpCas9 vs xCas9 PANCE evolution. Figure 2A, 96 well PANCE format allowed for simultaneous evolution of all 64 PAM sequences. PANCE is lower stringency than PACE as it is not continuous flow, thereby allowing for evolution from low activity. Figure 2B, data (luciferase assay) for PANCE evolution at passage 2 (P2), passage 12 (P12), and passage 16 (P16) for SpCas9 (wt) or xCas9 show an increase in the ability to bind additional PAM sequences.

[0009] Figures 3A-B show clones resulting from PANCE evolution experiments using SpCas9 (N3) after passage 12, including the activity for selected clones. Figure 3A, is a table listing individual clones and their mutations as compared to nuclease inactive SpCas9. The nomenclature of each clone indicates the PAM on which the clone was evolved. For example, clones CAA-2, CAA-3, and CAA-4 were evolved using a 5¢-CAA-3¢-PAM sequence. Figure 3B, shows activity for clones SpCas9, CAA-3, GAT-2, ATG-2, ATG-3, and AGC-3, using a luciferase assay. Clones were obtained from PANCE evolution experiments using SpCas9 (N3) after passage 12.

[0010] Figures 4A-B show clones resulting from PANCE evolution experiments using SpCas9 (N3) after passage 19, including the activity for selected clones. Figure 4A, is a table listing individual clones and their mutations as compared to nuclease inactive SpCas9. The nomenclature of each clone indicates the PAM on which the clone was evolved. For example, clones ACG-1, ACG-2, ACG-3, and ACG-4 were evolved using a 5¢-ACG-3¢-PAM sequence. Figure 4B, shows activity for clones SpCas9, N3.19.CAA1, N3.19.CAA2, N3.19.GAA1, N3.19.GAA2, N3.19.GAC5, N3.19.GAT1, N3.19.GAT3, N3.19.ACG1, N3.19.ACG3, N3.19.ACG6, N3.19.ATG3, and

N3.19.ATG6 using a luciferase assay. Clones were obtained from PANCE evolution experiments using SpCas9 (N3) after passage 19.

[0011] Figures 5A-B show clones resulting from PANCE evolution experiments using xCas9 3.7 (N4) after passage 12, including the activity for selected clones. Figure 5A, is a table listing individual clones and their mutations as compared to xCas93.7. The table indicates the PAM on which each of the clones was evolved. For example, clones N4.12.10 TAT1, N4.12.10 TAT2, and N4.12.10 TAT3 were evolved using a 5¢-TAT-3¢-PAM sequence. Figure 5B, shows activity for clones xCas9 (xCas93.7), TAT-1, TAT-3, GTA-1, GTA-3, and CAC-2 using a luciferase assay. Clones were obtained from PANCE evolution experiments using xCas93.9 (N4) after passage 12.

[0012] Figures 6A-B show clones resulting from PANCE evolution experiments using xCas93.7 (N4) after passage 19, including the activity for selected clones. Figure 6A, is a table listing individual clones and their mutations as compared to xCas93.7. The table indicates the PAM on which each of the clones was evolved. For example, clones N4.19.AAA1, N4.19.AAA2,

N4.19.AAA4, and N4.19.AAA7 were evolved using a 5¢-AAA-3¢-PAM sequence. Figure 6B, shows activity for N4.19.AAA1, N4.19.TAA2, N4.19.TAA5, N4.19.TAT5, N4.19.CAC5, N4.19.CAC6, N4.19.GTA2, N4.19.GTA7, N4.19.GCC2, N4.19.GCC5, and N4.19.GCC8 using a luciferase assay. Clones were obtained from PANCE evolution experiments using xCas93.9 (N4) after passage 19.

[0013] Figure 7 shows the results of mammalian cell editing using cytidine base editor BE3 having various evolved Cas9 clones (top). Indel formation for each of the clones as nuclease active Cas9s is also provided (bottom).

[0014] Figure 8 shows activity data (luciferase assay) for PANCE evolution experiments after passage 2 (N6.2), passage 12 (N6.12) and passage 16 (N6.16) using N4.12.TAT1 as the starting clone (N6). Increased shading indicates increased activity as described in Figure 1C.

[0015] Figures 9A-B show the mutations of TAT1 well as activity data (luciferase assay) on all 64 possible PAM sequences. Figure 9A provides the individual mutations of N4.12.TAT1 (TAT1) as compared to SpCas9. Figure 9B shows activity of TAT1 on all 64 possible PAM sequences.

Increased shading indicates increased activity as described in Figure 1C.

[0016] Figure 10 shows clones of resulting from PANCE evolution experiments using N4.12.TAT1 (N6) after passage 12. The individual mutations in clones N6.12.6, N6.12.7, N6.12.25, and N6.12.28, are shown as compared to TAT1. [0017] Figure 11 shows clones of resulting from PANCE evolution experiments using

N4.12.TAT1 (N6) after passage 18. The individual mutations for each of the listed clones (e.g., N6.18.1-1, N6, 18.1-2, etc.), are shown as compared to TAT1.

[0018] Figure 12 shows activity for N6.18.17-2, N6.18.18-2, N6.18.18-3, N6.18.28-2, N6.18.33-3, N6.18.39-1, N6.18.39-3, N6.18.39-4, N6.18.40-2, N6.18.40-3, N6.18.44-1, SP047a, and SpCas9. using a luciferase assay. Clones were obtained from PANCE evolution experiments using N4.12.TAT1 (N6) after passage 18 (See Figure 11).

[0019] Figures 13A-B show a split-intein PACE configuration to allow evolution of two separate activities of interest. Figure 13A shows that the bacteriophage gIII gene that produces the pIII protein is split into N-terminal (g3N) and C-terminal (g3C) fragments in two separate accessory plasmids (AP1 and AP2). AP1 and AP2 have the same PAM, but a different protospacer (it is not required that they have the same PAM, i.e., both the PAM and protospacer could be changed). Figure 13B shows the workflow for using a split-intein PACE configuration of the gIII gene.

[0020] Figures 14A-C show the evolution and activity of SpCas9 resulting from PACE

experiments using two separate protospacers and split-intein fusion (two allow evolution on two protospacers) as in Figures 13A-B. Figure 14A shows clones resulting from PACE evolution experiments using two protospacers with SpCas9 after passage 4 (P4). Figure 14B shows the ability of the P4 SpCas9 variants incorporated into a BE4max base-editor to support conversion of C to T in CAG, CAT, GAT, CAA, GAA, CGT, or GGG PAMs. Figure 14C shows the ability of the L2-72-4 SpCas9 P4 clone to form insertions or deletions in CAA1, CAA2, AAA1, AAA2, TAA1, TAA2, CAG1, CAG2, GAT1, GAT2, TAT1, TAT2, CAT, GAA1, GAA2, CGT, and GGG PAMs.

[0021] Figures 15A-B show a split-intein PACE configuration (whereby Cas9 is divided into two parts to limit Cas9 concentration) to allow evolution of Cas9 proteins of interest. Figure 15A shows that increasing the SpCas9 concentration increases cleavage of alternative (NAG) PAMs (as reported in Karvelis, T., Gasiunas, G., Young, J., Bigelyte, G., Silanskas, A., Cigan, M., and Siksnys, V. (2015). Rapid characterization of CRISPR-Cas9 protospacer adjacent motif sequence elements. Genome Biol. 16, 253). Figure 15B shows that the amount of Cas9 protein may be limited in PACE by splitting the inactive Cas9 protein (dCas9) into an N-terminal fragment (dCas9 (1-573)) and a C-terminal fragment (dCas9 (573-end)) and producing the N-terminal fragment from a low-copy number plasmid with a weak promoter (rpoZ).

[0022] Figure 16 shows clones resulting from PACE evolution when a split-intein Cas9 protein with the P4.2.72.4. mutations Experiment P10). The individual mutations for each of the listed clones (e.g., L5.144.2, L5.144.6, etc.), are shown as compared to spCas9 and spCas9 with the P4.2.72.4. mutations.

[0023] Figure 17 shows the ability of the P10 SpCas9 variants from Figure 16 incorporated into a BE4max base-editor to support conversion of C to T in CAG, GAT, TAT, CAT, GAA, CAA-1, or CAA-2 PAMs.

[0024] Figure 18 shows the ability of two P10 SpCas9 variants (P10.5.144.2 and P10.6.144.2) to form insertions or deletions in CAA1, CAA2, AAA1, AAA2, TAA1, TAA2, CAG1, CAG2, GAT1, GAT2, TAT1, TAT2, CAT, GAA1, GAA2, CGT, and GGG PAMs compared to a P4 variant (L2-72-4), SpCas9, and xCas9.

[0025] Figures 19A-C show characterization of a P10 SpCas9 variant with PAM depletion in E. coli. Figure 19A shows a workflow for PAM depletion in E. coli, wherein E. coli containing a Cas9 variant (e.g., P10) are transformed with a library of negative selection plasmids (e.g., pUC ampR with HEK3 protospacer followed by NNNN). See Kleinstiver et al., Engineered CRISPR-Cas9 nucleases with altered PAM specificities, Natur, 523: 481-485. The transformed cells are recovered and Cas9 expression is induced for 1-4 hours. The cells are then plated on carbenicillin media. The plates are then scraped and surviving colonies are sequenced for mutations. Colonies that survive and are sequenced contain PAMs that the P10 Cas9 variant protein could not cut. Figure 19B shows the frequency of PAM sequences present in surviving colonies, wherein more shaded PAM sequences occur more frequently (left), and the activity of P10 Cas9 variant protein on the PAM sequences in a luciferase assay (right). Figure 19C the activity of the P10 SpCas9 variants were characterized by PAM depletion incorporated into a BE4max base-editor to support conversion of C to T in CAG, CAT, GAT, CAA, GAA, CGT, or GGG PAMs

[0026] Figure 20 shows a characterization of the P10 SpCas9 variant protein following PAM depletion as in Figures 19A-19C. The P10 SpCas9 variant protein (left) and xCas9 variant proteins (middle) show preference for the fourth nucleotide in the PAM, wherein C is the most preferred and G is the least preferred. The spCas9 protein (right) does not show this preference. Higher Cas9 protein activity is denoted by darker shading.

[0027] Figure 21 shows clones resulting from split-intein PACE evolution of Cas9 with the P4.2.72.4 mutations Experiment P11) with a AAA PAM. The individual mutations for each of the listed clones (e.g., P11.1.139-2, P11.1.139-4, etc.), are shown as compared to spCas9 with the P4.2.72.4. mutations.

[0028] Figure 22 shows the ability of the P11 SpCas9 variants from Figure 16 incorporated into a BE3 base-editor to support conversion of C to T in CAG, GAT, CAT, GAA, AAA-1, AA1-2, CAA-1, CAA-2, or GGG PAMs.

[0029] Figure 23 shows the ability of two P11 SpCas9 variants (P11-SacB-1 and P11-SacB-2) to form insertions or deletions in CAA1, CAA2, AAA1, AAA2, TAA1, TAA2, CAG1, CAG2, GAT1, GAT2, TAT1, TAT2, CAT, GAA1, GAA2, CGT, and GGG PAMs compared to a P4 variant (L2-72-4), SpCas9, and xCas9.

[0030] Figures 24A-B show clones resulting from split-intein PACE evolution of Cas9 with P12 mutations on AAT (FIG.24A) or TAT (FIG.24B) PAMs. The individual mutations for each of the listed clones (e.g., P12.3.b9-2, P12.3.b10-2 etc.), are shown as compared to spCas9 protein.

[0031] Figures 25A-B show the ability of the P12 SpCas9 variants from Figures 24A-B

incorporated into a BE3 base-editor to support conversion of C to T at sites s893, s1073, s1081, s1140, b3, e1, e2, f1, f2, s33, s34, s35, s36, s37, s38, s39, s40, s41, s43, s44, s45, or s46. Darker shading indicates a higher % of C to T editing (FIG.25A). Figure 25B shows the average C to T editing on NATA, NATT, NATC, or NATG PAMs. pSM060ax is clone P12.3.b9-8 and pSM060ay is clone P12.3.b10-6.

[0032] Figures 26A-B show the ability of two P12 SpCas9 variants (P12.3.b9-8 and P12.3.b10-6) to cleave DNA in bacterial PAM depletion in AAA, AAC, AAT, AAG, CAA, CAC, CAT, CAG, TAA, TAC, TAT, TAG, GAA, GAT, GAG, AGA, AGC, AGT, AGG, CGA, CGC, CGT, CGG, TGA, TGC, TGT, TGG, GGA, GGC, GGT, or GGG PAMs. PPDV is the PAM frequency after Cas9

cutting/frequency of input library, wherein lower numbers signify more active Cas9 proteins.

[0033] Figures 27A-B show a split-intein PACE configuration to allow evolution of Cas9 proteins of interest with 2 protospacers. Figure 27A shows evolution of a split-intein Cas9 using selection on 2 protospacers. A second gene (gVI) is removed from the phage and is used as a selection marker on AP2. AP1 and AP2 have the same PAM, but different protospacers and a different nucleotide immediately 3’ of the PAM. Figure 27B shows clones resulting from split-intein PACE evolution of Cas9 as in Figure 27A. The individual mutations for each of the listed clones (e.g., L2-120-1, L2- 120-2, etc.), are shown as compared to spCas9 protein.

[0034] Figure 28 shows survival-based selection for isolating nuclease-active Cas9 variant proteins. In this selection, cutting identifies nuclease-active PACE variants. SacB is lethal in the presence of sucrose unless it is cut by Cas9, sfGFP loses fluorescence if Cas9 cutting occurs, and kanR confers survival on kanamycin medium if no cutting occurs.

[0035] Figures 29A-B show nuclease-active TAT variants that were identified by SacB selection as in Figure 28. The original spCas9 TAT variant was isolated from PANCE evolution on a TAT PAM (N4.TAT.1), but had no nuclease activity. This N4.TAT.1 (TAT1) Cas9 variant was subcloned from the pool of N4.TAT SP (H840-onward) into a Cas9 plasmid and selected for variants that could cut a SacB selection plasmid with a TAT PAM after a 4 hour induction. Figure 29A shows clones resulting from SacB selection of nuclease-inactive TAT. The individual mutations for each of the listed clones (e.g., SacB-TAT-1, SacB-TAT-2), are shown as compared to SpCas9 and TAT SpCas9 variant proteins. Figure 29B shows the location of mutations in the TAT SpCas9 variant proteins.

[0036] Figures 30A-B show the activity of the TAT SpCas9 variant proteins identified in Figure 29A. Figure 30A shows the ability of the nuclease-active TAT SpCas9 variants (SacB-TAT1 and SacB-TAT2) incorporated into a BE4max base-editor to support conversion of C to T in CAG, GAT, TAT, CAT, GAA-1, GAA-2, CAA-1, CAA-2, or GGG PAMs. Figure 30B shows ability of the SacB- TAT1 and SacB-TAT2 variants to form PAM depletion in CAA1, CAA2, AAA1, AAA2, TAA1, TAA2, CAG1, CAG2, GAT1, GAT2, TAT1, TAT2, CAT, GAA1, GAA2, CGT, or GGG PAMs.

[0037] Figure 31 shows the ability of the SacB-TAT-1 SpCas9 protein variant to form insertions or deletions in AAA, AAC, AAT, AAG, CAA, CAC, CAT, CAG, TAA, TAC, TAT, TAG, GAA, GAT, GAG, AGA, AGC, AGT, AGG, CGA, CGC, CGT, CGG, TGA, TGC, TGT, TGG, GGA, GGC, GGT, or GGG PAMs. PPDV is the PAM frequency after Cas9 cutting/frequency of input library, wherein lower numbers signify more active Cas9 proteins.

[0038] Figure 32 shows the location of frequently mutagenized residues by PAM selection.

Positions commonly mutated in SpCas9 variants obtained when evolving on NAN PAMs include: D1135, E1219, D1332.

[0039] Figures 33A-33D show C to T base editing with evolved variants on PAMs. C to T base editing with SpCas9 variants were incorporated into Be4MAX architecture in HEK293T cells. Figure 33A shows C to T base editing with NAA PAMs. Figure 33B shows C to T base editing with NAC PAMs. Figure 33C shows C to T base editing with NAT PAMs. Figure 33D shows C to T base editing with NAG PAMs. Each bar represents the average of 3 independent experiments, and the error bars represents the standard deviation. The“es” SpCas9 variant protein works best on NARH PAMs, with some activity on NARG and NGN PAMS, the“fn” SpCas9 variant protein works best on NRCH PAMs, with some activity on NRCG and NGN PAMs, and the“ax” SpCas9 variant protein works best on NRTH PAMs, with some activity on NRTG and NGN PAMs.

[0040] Figures 34A-34B show C to T base editing with evolved SpCas9 variants on PAMs. C to T base editing with SpCas9 variants were incorporated into BE4MAX architecture in HEK293T cells. Figure 34A shows C to T base editing on NAA, NAC, and NAT PAMs. Figures 34B shows C to T base editing on NAAH, NACH, and NATH PAMs, where H is any base except for G. Each bar represents the average of 3 independent experiments, and the error bars represents the standard deviation.

[0041] Figures 35A-35C show A to G base editing with evolved SpCas9 variants on PAMs. A to G base editing with SpCas9 variants incorporated into ABEMAX architecture in HEK293T cells. Figure 35A shows A to G base editing on NAA/NGA PAMs with es variant SpCas9. Figure 35B shows A to G base editing on NAC/NGC PAMs with fn variant SpCas9. Figure 35C shows A to G base editing on NAG/NGG PAMs with es and fn variant SpCas9 proteins. Each bar represents the average of 2 independent experiments, and the error bars represent the standard deviation.

[0042] Figure 36 show phage-assisted non-continuous evolution (PANCE) of SpCas9 binding activity on non-G PAMs. (A) Original selection scheme for Cas9 DNA binding. w-dSpCas9 expressed by DgIII selection phage (SP) binds to a designated protospacer/PAM sequence upstream of gIII on an accessory plasmid (AP) in host E. coli cells. Host cells and infecting SP are continuously mutagenized by a mutagenesis plasmid (MP). (B) Fold propagation of SP expressing w-dSpCas9 or w-dxCas9 on APs encoding each of all 64 NNN PAM sequences upstream of gIII. (C) Schematic overview of PANCE workflow. Host cells containing an AP and MP are grown to log phase in a deep well plate or tube before being infected with SP. Mutagenesis is induced and SP are allowed to propagate for 6-18 hours before cells are pelleted and the SP-containing supernatant is collected. The SP pool is then used to infect host cells in the next iteration of PANCE. (D) Consensus mutations arising from evolution of w-dSpCas9 (N1) or w-dxCas9 (N2) on NAA (red), NAT (blue), or NAC (green) PAM sequences.

[0043] Figures 37A-37E shows multiple new PACE schemes utilizing a split-intein Cas9 and/or two protospacers. Figure 37A shows new PACE schemes to limit the concentration of spCas9 protein and/or increase the number of Cas9 binding sites. Figure 37B shows SpCas9 individual NAA mutations for each of the listed clones (e.g., N3.GAA-3, N3.GAA-4, etc.), are shown as compared to SpCas9 protein. Figure 37C shows a timecourse of the NAA variants from Figure 37B through evolution. Figure 37D shows SpCas9 individual NAC mutations for each of the listed clones (e.g., N4.CAC-1, N4.CAC-5, etc.), are shown as compared to SpCas9 protein. Also shown is D1135N, R1114G, V1139A, E1219V, Q1221H, R1320V, and R1333K mapped to the SpCas9 crystal structure 4un3. Figure 37E shows SpCas9 individual NAT mutations for each of the listed clones (e.g., SacB.N4.TAT-1, SacB.N4-TAT-3, etc.), are shown as compared to SpCas9 protein. Also shown is D1135N, R1114G, E1219V, H1349R, S1338T, R1335Q, and D1332N mapped to the SpCas9 crystal structure 4un3 (left, lower structure). The lower right structure also shows D1135N, R1114G, E1219V, G1218S, Q1221H, P1321S, R1335, and D1332G mapped to the SpCas9 crystal structure 4un3.

[0044] Figures 38A-38D show characterization of evolved variants and SpCas9-NG through bacterial PAM depletion and mammalian cell indel formation. Figure 38A shows bacterial PAM depletion of SpCas9-NRRH, -NRTH, -NRCH, and SpCas9-NG using a bacterial NNNN PAM library. The inverse of the depletion score was used to generate enrichment scores of activity on each NNNN PAM, which were then used to create sequence logos (WebLogo3.0). Figure 38B shows indel formation in HEK293T cells across 64 endogenous mammalian sites containing NANN PAMs for SpCas9-NRRH, -NRTH, -NRCH, and SpCas9-NG. Mean and SE of three independent biological replicates are shown. Figure 38C provides a summary of indel formation efficiencies in HEK293T cells across 48 endogenous mammalian sites containing NANH (H=non-G) PAMs for SpCas9-NRRH, -NRTH, -NRCH, and SpCas9-NG. Mean and standard deviation (SD) of all individual values of three independent biological replicates are plotted. Figure 38D shows DNA targeting specificity of SpCas9, xCas9, and evolved variants SpCas9-NRRH, -NRTH-, and NRCH as determined by % on- target reads resulting from GUIDE-seq analysis using HEK target site 4 in U2OS cells.

[0045] Figure 39A-39E show mammalian C to T and A to G base editing activity of evolved variants and SpCas9-NG. Figure 39A shows cytosine base editing in HEK293T cells across 64 endogenous mammalian sites containing NANN PAMs for BE4-NRRH, BE4-NRTH, BE4-NRCH, and BE4-NG. Mean and SE of three independent biological replicates are shown. Figure 39B shows a summary of cytosine base editing in HEK293T cells across 48 endogenous mammalian sites containing NANH (H=non-G) PAMs for BE4-NRRH, BE4-NRTH, BE4-NRCH, and BE4-NG. Mean and SE of three independent biological replicates are shown. Figure 39C shows adenine base editing in HEK293T cells across 27 endogenous mammalian sites containing NANN PAMs for ABE- NRRH, ABE-NRTH, ABE-NRCH, and ABE-NG. Mean and SE of three independent biological replicates are shown. Figure 39D shows the fraction of pathogenic SNPs in the ClinVar Database that could in principle be corrected by a C•G to T•A (left) or A•T to G•C (right) base conversion using NR PAMs. Figure 39E shows the number of possible sgRNAs capable of targeting pathogenic SNPs in the ClinVar Database using NR, NG, or NGG PAMs.

[0046] Figures 40A-40G shows a characterization of PAM preferences using a genomically integrated human cell base editing target sequence library. Figure 40A is a schematic overview of a mammalian cell base editing library experiment. A library of matched sgRNA/protospacer target sites spanning all NNNN PAMs is stably genomically integrated in HEK293T cells. Library cells are then transfected with and selected for genomic integration of plasmids encoding BE4 variants. After antibiotic selection, cells are lysed and the integration of plasmids encoding BE4 variants. After antibiotic selection, cells are lysed and the integrated sgRNA/protospacer site is PCR amplified for HTS analysis. Figure 40B provides a heat map of base editing activity on the NNNN PAM library in HEK293T cells, with positions 2, 3, and 4 of the PAM defined. For each construct, the mean editing across all sites containing the designated PAM over two independent biological replicates, internally normalized against the highest editing value for each construct, is shown.

Figure 40C-E shows the average base editing activity on the NNNN PAM library in HEK293T cells by BE4, BE4-NRRH, BE4-NRTH, and BE4-NRCH, with PAM positions 2 (C), position 3 (D), or position 4 (E) fixed. Mean and SE for individual editing values (averaged across two independent biological replicates) at all relevant library sequences are shown. Figure 40F-40G show the effect of sgRNA length and 5’G mismatches on the base editing efficiency of profiled SpCas9 variants. The percentage decrease of editing efficiency from using a 21 nt sgRNA with either a mached (F) or mismatched (G) 5’G compared to using a matched 20 nt sgRNA is shown for BE4, BE4-NRRH, BE4- NRCH, BE4-NRTH, and BE4-NG on all library sequences containing NAN, NRN, NGN, or NGG PAMs. The mean and SE are plotted.

[0047] Figure 41A-41C shows evolved SpCas9 variants allow correction of pathogenic SNPs using non-G PAMs. Figure 41A provides an overview of adenine base editing strategy for correcting the sickle hemoglobin (HbS) SNP. In HbS, the Glu (GAG codon) at position 6 of normal b-globin (HBB) is mutated to a Val (GTG codon). Targeting this SNP with A•T to G•C base editing on the reverse strand enables a Val to Ala (GTG to GCG) base conversion, leading to the Makassar b-globin variant (HbG) which produces phenotypically normal b-globin. Figure 41B shows A•T to G•C base editing in HEK293T cells engineered with the HbS mutation using a CACC PAM by ABE- NRRH, ABE-NRTH, ABE-NRCH, and ABE-NG. This PAM places the target A at position 7, and an off-target A, which leads to a silent pro (CCT) to pro (CCC) mutation, at position 9. Mean and SE of three independent biological replicates are shown. Figure 41C shows A•T to G•C base editing in HEK293T cells engineered with the HbS mutation using a CATG PAM by ABE-NRRH, ABE-NRTH, ABE-NRCH, and ABE-NG. This PAM places the target A at position 4, and an off-target A, which leads to a silent pro (CCT) to pro (CCC) mutation, at position 6. Mean and SE of three independent biological replicates are shown.

[0048] Figure 42 provides a table of NRNN PAM targeting potential by SpCas9 and SaCs9 variants described herein. The variants SpCas9-NRRH, SpCas9-NRTH, and SpCas9-NRCH are disclosed and discussed herein.

[0049] Figure 43A-43F depicts additional details of Cas9:DNA binding PACE and Cas9 nuclease selections. Figure 43A shows dual AP selection where ώ-dSpCas9 binds two distinct

protospacer/PAM sequences to drive either half of split-intein pIII. Figure 43B shows split-intein Cas9 limits total Cas9 concentration in host cells, thus avoiding saturation of protospacer/PAM binding sites. Residues 574-1368 of Cas9 fused to NpuC is expressed by DgIII SP and ώ–dSpCas9(1- 573) fused to NpuN is encoded on a low copy complimentary plasmid (CP) in host cells. Figure 43C shows a combination of the selection principles from (A) and (B) through use of gVI as an additional PACE-compatible selection marker for phage propagation and DgIIIDgVI SP. Figure 43D shows overnight propagation assay of selection phage (SP) encoding dSpCas9C on host cells containing a complimentary plasmid (CP) providing either ώ–dSpCas9 _N or ώ–dSpCas9 _N-mut and an AP encoding either a AAA or CAA PAM. Figure 43E and 43F show a scheme of survival based selection for Cas9 nuclease activity. Cells containing a high-copy selection plasmid encoding a protospacer/ PAM sequence, sfGFP, and the conditionally lethal protein SacB are transformed with a library of nuclease-active Cas9s encoded on a low-copy plasmid that also includes the matching sgRNA.

Binding and cleavage of the designated PAM/protospacer by Cas9 leads to destruction of the selection plasmid, resulting in loss of both sfGFP and SacB expression, allowing cells to survive on sucrose- containing media.

[0050] Figure 44A-44C show the effects of mutations on PAM recognition by SpCas9 variants. Figure 44A shows the addition of the Y1131C mutation, which was enriched in the later phases of the NAT evolution trajectory, inactivates BE3-NRTH in HEK293T cells. Mean and SE of three independent biological replicates are shown. Figure 44B shows the N-terminal mutations of SpCas9-NRRH, -NRCH, and -NRTH mapped to the SpCas9 crystal structure (4UN3). Figure 44C shows CBE activity of BE3-NRRH, BE3-NRTH, and BE3-NRCH with and without the N-terminal mutations shown in (B) in HEK293T cells. Mean and SE of three independent biological replicates are shown.

[0051] Figure 45A-45D is a characterization of SpCas9, xCas9, and evolved variants (SpCa9- NRTH, SpCas9-NRCH, and SpCas9-NRRH) in bacterial PAM depletion and mammalian indel formation experiments. Figure 45A shows bacterial PAM depletion of SpCas9-NRRH, -NRCH, - NRTH, and SpCas9-NG on a bacterial NNNN PAM library with 1 h, 3 h, and overnight Cas9 induction. The inverse of the depletion score was used to generate enrichment scores of activity on each NNNN PAM, which were then used to create sequence logos (WebLogo3.0). Figure 45B shows indel formation in HEK293T cells across endogenous mammalian sites containing NANN PAMs for xCas9, SpCas9-NRRH, -NRTH, -NRCH, and SpCas9-NG. Mean and SE of three independent biological replicates are shown. Figure 45C shows indel formation in HEK293T cells across endogenous mammalian sites containing NGNN PAMs for SpCas9-NRRH, -NRTH, -NRCH, SpCas9-NG, and SpCas9. Mean and SE of three independent biological replicates are shown. Figure 45D shows GUIDE-seq analysis of SpCas9, xCas9, and evolved variants SpCas9-NRRH, -NRTH, and -NRCH targeting HEK site 4 in U2OS cells. GUIDE-seq on-target (indicated by the asterisk) and off-target reads that are greater than or equal to 1% total reads are shown.

[0052] Figure 46A-46C shows the characterization of SpCas9 (BE4), SpCas9-NG (BE4-NG), and evolved CBE and ABE variants in mammalian base editing experiments. Figure 46A shows CBE in HEK293T cells across endogenous mammalian sites containing NGNN PAMs for BE4-NRRH, BE4- NRTH, BE4-NRCH, BE4-NG, and BE4. Mean and SE of three independent biological replicates are shown. Figure 46B shows ABE in HEK293T cells across endogenous mammalian sites containing NGNN PAMs for ABE-NRRH, ABE-NRTH, ABE-NRCH, and ABE-NG. Mean and SE of three independent biological replicates are shown. For target sites with NGA, NGC, and NGT PAMs, only ABE-NRRH, ABE-NRTH, and ABE-NRCH are shown, respectively, in addition to SpCas9-NG. Figure 46C shows the fraction of pathogenic SNPs in the ClinVar Database with either a single targetable base within the window or multiple targetable bases that could in principle be corrected by a C•G to T•A (top left) or A•T to G•C (top right) base conversion using NR PAMs or C•G to T•A (bottom left) or A•T to G•C (bottom right) base conversion using NG PAMs.

[0053] Figure 47A-47D shows the characterization of PAM preferences of BE4, BE4-NRRH, BE4- NRCH, and BE4-NG using a genomically integrated human cell base editing target sequence library Figure 47A shows the distribution of the number of target sites per PAM within the integrated sgRNA library. Figure 47B shows the PAM preferences for BE4, BE4-NRRH, BE4-NRTH, and BE4- NRCH as determined by base editing on the target sequence library integrated in HEK293T cells. Sequence logos for each construct were created from the CBE activity on each NNNN PAM contained in the library (WebLogo3.0). Figure 47C Average base editing activity on the NNNN PAM library in HEK293T cells by BE4, BE4-NRRH, BE4-NRTH, and BE4-NRCH, with PAM position 1 fixed. Mean and SE for individual editing values (averaged across two independent biological replicates) at all relevant library sequences are shown. Figure 47C-47D shows effect of sgRNA length and 5’G mismatch on base editing efficiency of profiled SpCas9 variants. Average base editing on the NNNN PAM library in HEK293T cells by BE4, BE4-NRRH, BE4-NRTH, and BE4-NRCH is grouped by sites containing a 20-nt sgRNA with a 5’G matched to the target sequence, a 21-nt sgRNA with a 5’G matched to the target sequence, or a 21-nt sgRNA with a mismatched 5’ nucleotide.

Average editing activity of constructs on NGN (Figure 47D), NAN (Figure 47E), and NGG (Figure 47F) PAMs are shown. Mean and SE for individual editing values (averaged across two independent biological replicates) at all relevant library sequences are shown. ns, not significant; *, p < 0.05; **, p < 0.01; ***, p < 0.001 (Student’s t test). [0054] Figure 48A-48C shows high-throughput sequencing analysis of sickle cell locus editing by SpCas9 variant-derived ABEs. Figure 48A shows Crispresso2 output showing the HbS mutation in a engineered HEK293T cell line. HEK293T cells were treated with nickase-SpCas9, sgRNA (binding shown in grey), and ssODN containing the point mutation. After two rounds of transfection, sorting, and growth, the cell line sequenced above was isolated and identified to have 100% conversion to the sickle cell anemia allele. Figure 48B shows Crispresso2 output showing ABE activity of ABE-NRRH, ABE-NRTH, ABE-NRCH, and ABE-NG in HbS engineered HEK293T cells using a sgRNA (gray bar) targeting a CATG PAM. Figure 48C shows Crispresso2 output showing ABE activity of ABE-NRRH, ABE-NRTH, ABE-NRCH, and ABE-NG in HbS engineered HEK293T cells using a sgRNA (gray bar) targeting a CACC PAM. DEFINITIONS

[0055] As used herein and in the claims, the singular forms“a,”“an,” and“the” include the singular and the plural reference unless the context clearly indicates otherwise. Thus, for example, a reference to“an agent” includes a single agent and a plurality of such agents.

[0056] The term“base editor (BE),” or“nucleobase editor (NBE),” as used herein, refers to an agent comprising a polypeptide that is capable of making a modification to a base (e.g., A, T, C, G, or U) within a nucleic acid sequence (e.g., DNA or RNA). In some embodiments, the base editor is capable of deaminating a base within a nucleic acid. In some embodiments, the base editor is capable of deaminating a base within a DNA molecule. In some embodiments, the base editor is capable of deaminating a cytosine (C) in DNA. In some embodiments, the base editor is a fusion protein comprising a nucleic acid programmable DNA binding protein fused to a nucleic acid editing domain. In some embodiments, the base editor is a fusion protein comprising a nucleic acid programmable DNA binding protein (napDNAbp) fused to a cytidine deaminase domain. In some embodiments, the base editor comprises a Cas9 domain (e.g., an evolved Cas9 domain), or an evolved version of a CasX, CasY, Cpf1, C2c1, C2c2, C2c3, or Argonaute protein that comprises one or more mutations homologous to the mutations provided herein fused to a cytidine deaminase. In some embodiments, the base editor comprises a Cas9 nickase (Cas9n) fused to an cytidine deaminase domain. In some embodiments, the base editor comprises a nuclease-inactive Cas9 (dCas9) fused to a cytidine deaminase domain. In some embodiments, the base editor includes an inhibitor of base excision repair, for example, a UGI domain or a dISN domain.

[0057] In some embodiments, the base editor is capable of deaminating an adenosine (A) in DNA. In some embodiments, the base editor is a fusion protein comprising a nucleic acid programmable DNA binding protein fused to a nucleic acid editing domain. In some embodiments, the base editor is a fusion protein comprising a nucleic acid programmable DNA binding protein (napDNAbp) fused to an adenosine deaminase domain. In some embodiments, the base editor is a fusion protein comprising a nucleic acid programmable DNA binding protein (napDNAbp) fused to one or more adenosine deaminase domains. In some embodiments, the base editor is a fusion protein comprising a nucleic acid programmable DNA binding protein (napDNAbp) fused to two adenosine deaminase domains. In some embodiments, the base editor comprises a Cas9 (e.g., an evolvedCas9 domain), or an evolved version of a CasX, CasY, Cpf1, C2c1, C2c2, C2c3, or Argonaute protein that comprises one or more mutations homologous to the mutations provided herein fused to an adenosine deaminase domain. In some embodiments, the base editor comprises a Cas9 nickase (Cas9n) fused to an adenosine deaminase domain. In some embodiments, the base editor comprises a Cas9 nickase (Cas9n) fused to two adenosine deaminase domains. In some embodiments, the base editor comprises a nuclease- inactive Cas9 (dCas9) fused to an adenosine deaminase domain. In some embodiments, the base editor comprises a nuclease-inactive Cas9 (dCas9) fused to two adenosine deaminase domains. In some embodiments, the base editor is fused to an inhibitor of base excision repair, for example, a UGI domain, or a dISN domain.

[0058] The term“nucleic acid programmable DNA binding protein” or“napDNAbp” refers to a protein that associates with a nucleic acid (e.g., DNA or RNA), such as a guide nucleic acid (e.g., gRNA), that guides the napDNAbp to a specific nucleic acid sequence, for example, by hybridizing to the target nucleic acid sequence. For example, a Cas9 domain can associate with a guide RNA that guides the Cas9 domain to a specific DNA sequence that has complementary to the guide RNA. In some embodiments, the napDNAbp is a class 2 microbial CRISPR-Cas effector. In some embodiments, the napDNAbp is a Cas9 domain, for example, a nuclease active Cas9, a Cas9 nickase (Cas9n), or a nuclease inactive Cas9 (dCas9). Examples of nucleic acid programmable DNA binding proteins include, without limitation, Cas9 (e.g., an evolved Cas9 domain), or an evolved version of a CasX, CasY, Cpf1, C2c1, C2c2, C2c3, or Argonaute protein that comprises one or more mutations homologous to the mutations provided herein. It should be appreciated, however, that nucleic acid programmable DNA binding proteins also include nucleic acid programmable proteins that bind RNA. For example, the napDNAbp may be associated with a nucleic acid that guides the napDNAbp to an RNA. Other nucleic acid programmable DNA binding proteins are also within the scope of this disclosure, though they may not be specifically described in this Application. [0059] As used herein, the term“circular permutant” refers to a protein or polypeptide (e.g., a Cas9) comprising a circular permutation, which is change in the protein’s structural configuration involving a change in order of amino acids appearing in the protein’s amino acid sequence. In other words, circular permutants are proteins that have altered N- and C-termini as compared to a wild-type counterpart, e.g., the wild-type C-terminal half of a protein becomes the new N-terminal half.

Circular permutation (or CP) is essentially the topological rearrangement of a protein’s primary sequence, connecting its N- and C-terminus, often with a peptide linker, while concurrently splitting its sequence at a different position to create new, adjacent N- and C-termini. The result is a protein structure with different connectivity, but which oftern can have the same overall similar three- dimensional (3D) shape, and possibly include improved or altered characteristics, including, reduced proteolytic susceptibility, improved catalytic activity, altered substrate or ligand binding, and/or improved thermostability. Circular permutant proteins can occur in nature (e.g., concanavalin A and lectin). In addition, circular permutation can occur as a result of posttranslational modifications or may be engineered using recombinant techniques.

[0060] The term“circularly permuted Cas9” refers to any Cas9 protein, or variant thereof, that has been occurs as a circular permutant, whereby its N- and C-termini have been topically rearranged. Such circularly permuted Cas9 proteins (“CP-Cas9”), or variants thereof, retain the ability to bind DNA when complexed with a guide RNA (gRNA). See, Oakes et al.,“Protein Engineering of Cas9 for enhanced function,” Methods Enzymol, 2014, 546: 491–511 and Oakes et al.,“CRISPR-Cas9 Circular Permutants as Programmable Scaffolds for Genome Modification,” Cell, January 10, 2019, 176: 254-267, each of are incorporated herein by reference. The instant disclosure contemplates any previously known CP-Cas9 or use a new CP-Cas9 so long as the resulting circularly permuted protein retains the ability to bind DNA when complexed with a guide RNA (gRNA).

[0061] In some embodiments, the napDNAbp is an“RNA-programmable nuclease” or“RNA- guided nuclease.” The terms are used interchangeably herein and refer to a nuclease that forms a complex with (e.g., binds or associates with) one or more RNA(s) that is not a target for cleavage. In some embodiments, an RNA-programmable nuclease, when in a complex with an RNA, may be referred to as a nuclease:RNA complex. Typically, the bound RNA(s) is referred to as a guide RNA (gRNA). Guide RNAs can exist as a complex of two or more RNAs, or as a single RNA molecule. Guide RNAs that exist as a single RNA molecule may be referred to as single-guide RNAs (sgRNAs), though“gRNA” is also used to refer to guide RNAs that exist as either single molecules or as a complex of two or more molecules. Typically, gRNAs that exist as a single RNA species comprise two domains: (1) a domain that shares homology to a target nucleic acid (i.e., directs binding of a Cas9 complex to the target); and (2) a domain that binds a Cas9 domain. In some embodiments, domain (2) corresponds to a sequence known as a tracrRNA and comprises a stem-loop structure. In some embodiments, domain (2) is identical or homologous to a tracrRNA as provided in Jinek et al., Science 337:816-821 (2012), the entire contents of which is incorporated herein by reference. Other examples of gRNAs (e.g., those including domain 2) can be found in International Patent Application PCT/US2014/054252, filed September 5, 2014, entitled“Switchable Cas9 Nucleases And Uses Thereof,” and International Patent Application PCT/US2014/054247, filed September 5, 2014, entitled“Delivery System For Functional Nucleases,” the entire contents of each are hereby incorporated by reference in their entirety. In some embodiments, a gRNA comprises two or more of domains (1) and (2), and may be referred to as an“extended gRNA.” For example, an extended gRNA will bind two or more Cas9 domains and bind a target nucleic acid at two or more distinct regions, as described herein. The gRNA comprises a nucleotide sequence that complements a target site, which mediates binding of the nuclease/RNA complex to said target site, providing the sequence specificity of the nuclease:RNA complex. In some embodiments, the RNA-programmable nuclease is the (CRISPR-associated system) Cas9 endonuclease, for example, Cas9 (also known as Csn1) from Streptococcus pyogenes (see, e.g.,“Complete genome sequence of an M1 strain of Streptococcus pyogenes.” Ferretti J.J., McShan W.M., Ajdic D.J., Savic D.J., Savic G., Lyon K., Primeaux C., Sezate S., Suvorov A.N., Kenton S., Lai H.S., Lin S.P., Qian Y., Jia H.G., Najar F.Z., Ren Q., Zhu H., Song L., White J., Yuan X., Clifton S.W., Roe B.A., McLaughlin R.E., Proc. Natl. Acad. Sci. U.S.A.

98:4658-4663 (2001);“CRISPR RNA maturation by trans-encoded small RNA and host factor RNase III.” Deltcheva E., Chylinski K., Sharma C.M., Gonzales K., Chao Y., Pirzada Z.A., Eckert M.R., Vogel J., Charpentier E., Nature 471:602-607 (2011); and“A programmable dual-RNA-guided DNA endonuclease in adaptive bacterial immunity.” Jinek M., Chylinski K., Fonfara I., Hauer M., Doudna J.A., Charpentier E. Science 337:816-821 (2012), the entire contents of each of which are incorporated herein by reference).

[0062] Because RNA-programmable nucleases (e.g., Cas9) use RNA:DNA hybridization to target DNA cleavage sites, these proteins are able to target, in principle, any sequence specified by the guide RNA. Methods of using RNA-programmable nucleases, such as Cas9, for site-specific cleavage (e.g., to modify a genome) are known in the art (see e.g., Cong, L. et al., Multiplex genome engineering using CRISPR/Cas systems. Science 339, 819-823 (2013); Mali, P. et al., RNA-guided human genome engineering via Cas9. Science 339, 823-826 (2013); Hwang, W.Y. et al., Efficient genome editing in zebrafish using a CRISPR-Cas system. Nature biotechnology 31, 227-229 (2013); Jinek, M. et al. RNA-programmed genome editing in human cells. eLife 2, e00471 (2013); Dicarlo, J.E. et al., Genome engineering in Saccharomyces cerevisiae using CRISPR-Cas systems. Nucleic Acids Research (2013); Jiang, W. et al., RNA-guided editing of bacterial genomes using CRISPR-Cas systems. Nature Biotechnology 31, 233-239 (2013); the entire contents of each of which are incorporated herein by reference).

[0063] In general, a“CRISPR system” refers collectively to transcripts and other elements involved in the expression of or directing the activity of CRISPR-associated (“Cas”) genes, including sequences encoding a Cas gene, a tracr (trans-activating CRISPR) sequence (e.g. tracrRNA or an active partial tracrRNA), a tracr mate sequence (encompassing a“direct repeat” and a tracrRNA- processed partial direct repeat in the context of an endogenous CRISPR system), a guide sequence (also referred to as a“spacer” in the context of an endogenous CRISPR system), or other sequences and transcripts from a CRISPR locus. The tracrRNA of the system is complementary (fully or partially) to the tracr mate sequence present on the guide RNA.

[0064] The term“Cas9” or“Cas9 nuclease” refers to an RNA-guided nuclease comprising a Cas9 domain, or a fragment thereof (e.g., a protein comprising an active or inactive DNA cleavage domain of Cas9, and/or the gRNA binding domain of Cas9). A“Cas9 domain” as used herein, is a protein fragment comprising an active or inactive cleavage domain of Cas9 and/or the gRNA binding domain of Cas9. A“Cas9 protein” is a full length Cas9 protein. A Cas9 nuclease is also referred to sometimes as a casn1 nuclease or a CRISPR (Clustered Regularly Interspaced Short Palindromic Repeat)- associated nuclease. CRISPR is an adaptive immune system that provides protection against mobile genetic elements (viruses, transposable elements, and conjugative plasmids). CRISPR clusters contain spacers, sequences complementary to antecedent mobile elements, and target invading nucleic acids. CRISPR clusters are transcribed and processed into CRISPR RNA (crRNA). In type II CRISPR systems correct processing of pre-crRNA requires a trans-encoded small RNA (tracrRNA), endogenous ribonuclease 3 (rnc) and a Cas9 domain. The tracrRNA serves as a guide for ribonuclease 3-aided processing of pre-crRNA. Subsequently, Cas9/crRNA/tracrRNA endonucleolytically cleaves linear or circular dsDNA target complementary to the spacer. The target strand not complementary to crRNA is first cut endonucleolytically, then trimmed 3¢-5¢ exonucleolytically. In nature, DNA-binding and cleavage typically requires protein and both RNAs. However, single guide RNAs (“sgRNA”, or simply“gNRA”) can be engineered so as to incorporate aspects of both the crRNA and tracrRNA into a single RNA species. See, e.g., Jinek M., Chylinski K., Fonfara I., Hauer M., Doudna J.A.,

Charpentier E. Science 337:816-821(2012), the entire contents of which are hereby incorporated by reference. Cas9 recognizes a short motif in the CRISPR repeat sequences (the PAM or protospacer adjacent motif) to help distinguish self versus non-self. Cas9 nuclease sequences and structures are well known to those of skill in the art (see, e.g.,“Complete genome sequence of an M1 strain of Streptococcus pyogenes.” Ferretti et al., J.J., McShan W.M., Ajdic D.J., Savic D.J., Savic G., Lyon K., Primeaux C., Sezate S., Suvorov A.N., Kenton S., Lai H.S., Lin S.P., Qian Y., Jia H.G., Najar F.Z., Ren Q., Zhu H., Song L., White J., Yuan X., Clifton S.W., Roe B.A., McLaughlin R.E., Proc. Natl. Acad. Sci. U.S.A.98:4658-4663(2001);“CRISPR RNA maturation by trans-encoded small RNA and host factor RNase III.” Deltcheva E., Chylinski K., Sharma C.M., Gonzales K., Chao Y., Pirzada Z.A., Eckert M.R., Vogel J., Charpentier E., Nature 471:602-607(2011); and“A programmable dual-RNA- guided DNA endonuclease in adaptive bacterial immunity.” Jinek M., Chylinski K., Fonfara I., Hauer M., Doudna J.A., Charpentier E. Science 337:816-821(2012), the entire contents of each of which are incorporated herein by reference). Cas9 orthologs have been described in various species, including, but not limited to, S. pyogenes and S. thermophilus. Additional suitable Cas9 nucleases and sequences will be apparent to those of skill in the art based on this disclosure, and such Cas9 nucleases and sequences include Cas9 sequences from the organisms and loci disclosed in Chylinski, Rhun, and Charpentier,“The tracrRNA and Cas9 families of type II CRISPR-Cas immunity systems” (2013) RNA Biology 10:5, 726-737; the entire contents of which are incorporated herein by reference. In some embodiments, a Cas9 nuclease comprises one or more mutations that partially impair or inactivate the DNA cleavage domain.

[0065] A nuclease-inactivated Cas9 domain may interchangeably be referred to as a“dCas9” protein (for nuclease-“dead” Cas9). Methods for generating a Cas9 domain (or a fragment thereof) having an inactive DNA cleavage domain are known (see, e.g., Jinek et al., Science.337:816-821(2012); Qi et al.,“Repurposing CRISPR as an RNA-Guided Platform for Sequence-Specific Control of Gene Expression” (2013) Cell.28;152(5):1173-83, the entire contents of each of which are incorporated herein by reference). For example, the DNA cleavage domain of Cas9 is known to include two subdomains, the HNH nuclease subdomain and the RuvC1 subdomain. The HNH subdomain cleaves the strand complementary to the gRNA, whereas the RuvC1 subdomain cleaves the non- complementary strand. Mutations within these subdomains can silence the nuclease activity of Cas9. For example, the mutations D10A and H840A completely inactivate the nuclease activity of S.

pyogenes Cas9 (Jinek et al., Science.337:816-821(2012); Qi et al., Cell.28;152(5):1173-83 (2013)). In some embodiments, proteins comprising fragments of Cas9 are provided. For example, in some embodiments, a protein comprises one of two Cas9 domains: (1) the gRNA binding domain of Cas9; or (2) the DNA cleavage domain of Cas9. In some embodiments, proteins comprising Cas9 or fragments thereof are referred to as“Cas9 variants.” A Cas9 variant shares homology to Cas9, or a fragment thereof. For example, a Cas9 variant is at least about 70% identical, at least about 80% identical, at least about 90% identical, at least about 95% identical, at least about 96% identical, at least about 97% identical, at least about 98% identical, at least about 99% identical, at least about 99.5% identical, at least about 99.8% identical, or at least about 99.9% identical to wild type Cas9 (e.g., SpCas9 of SEQ ID NO: 2). In some embodiments, the Cas9 variant may have 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 21, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, or more amino acid changes compared to wild type Cas9 (e.g., SpCas9 of SEQ ID NO: 2). In some embodiments, the Cas9 variant comprises a fragment of Cas9 (e.g., a gRNA binding domain or a DNA-cleavage domain), such that the fragment is at least about 70% identical, at least about 80% identical, at least about 90% identical, at least about 95% identical, at least about 96% identical, at least about 97% identical, at least about 98% identical, at least about 99% identical, at least about 99.5% identical, or at least about 99.9% identical to the corresponding fragment of wild type Cas9 (e.g., SpCas9 of SEQ ID NO: 2). In some embodiments, the fragment is at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95% identical, at least 96%, at least 97%, at least 98%, at least 99%, or at least 99.5% of the amino acid length of a corresponding wild type Cas9 (e.g., SpCas9 of SEQ ID NO: 2).

[0066] In some embodiments, proteins comprising fragments of Cas9 are provided. In some embodiments, the fragment is at least 100 amino acids in length. In some embodiments, the fragment is at least 100, 150, 200, 250, 300, 350, 400, 450, 500, 550, 600, 650, 700, 750, 800, 850, 900, 950, 1000, 1050, 1100, 1150, 1200, 1250, or at least 1300 amino acids in length. For example, in some embodiments, a protein comprises one of two Cas9 domains: (1) the gRNA binding domain of Cas9; or (2) the DNA cleavage domain of Cas9. In some embodiments, proteins comprising Cas9 or fragments thereof are referred to as“Cas9 variants.” A Cas9 variant shares homology to Cas9. For example a Cas9 variant is at least about 70% identical, at least about 80% identical, at least about 90% identical, at least about 95% identical, at least about 96% identical, at least about 97% identical, at least about 98% identical, at least about 99% identical, at least about 99.5% identical, or at least about 99.9% to wild type Cas9 (e.g., SpCas9 of SEQ ID NO: 2). In some embodiments, the Cas9 variant comprises a fragment of Cas9 (e.g., a gRNA binding domain or a DNA-cleavage domain), such that the fragment is at least about 70% identical, at least about 80% identical, at least about 90% identical, at least about 95% identical, at least about 96% identical, at least about 97% identical, at least about 98% identical, at least about 99% identical, at least about 99.5% identical, or at least about 99.9% to the corresponding fragment of wild type Cas9 (e.g., SpCas9 of SEQ ID NO: 2). In some embodiments, wild type Cas9 corresponds to Cas9 from Streptococcus pyogenes (NCBI Reference Sequence: NC_017053.1, SEQ ID NO: 1 (nucleotide); SEQ ID NO: 2 (amino acid)).

[0069] In some embodiments, Cas9 refers to a Cas9 nickase having a D10A substitution (e.g., S.

(single underline: HNH domain; double underline: RuvC domain)

[0070] In other embodiments, Cas9 refers to a Cas9 nickase having a H840A substitution (e.g., S.

DLSQLGGD (SEQ ID NO: 8) (single underline: HNH domain; double underline: RuvC domain; H840A mutation shown in bold) [0071] In still other embodiments, Cas9 refers to a dead Cas9 having D10A and H840A substitutions (e.g., S. pyogenes Cas9 Q99ZW2 (D10A) (H840A)) (SEQ ID NO: 9):

(D10A and H840A mutations shown in bold; see, e.g., Qi et al., Repurposing CRISPR as an RNA- guided platform for sequence-specific control of gene expression. Cell.2013; 152(5):1173-83, the entire contents of which are incorporated herein by reference).

[0072] In some embodiments, Cas9 refers to Cas9 protein derived from: Corynebacterium ulcerans (NCBI Refs: NC_015683.1, NC_017317.1); Corynebacterium diphtheria (NCBI Refs: NC_016782.1, NC_016786.1); Spiroplasma syrphidicola (NCBI Ref: NC_021284.1); Prevotella intermedia (NCBI Ref: NC_017861.1); Spiroplasma taiwanense (NCBI Ref: NC_021846.1); Streptococcus iniae (NCBI Ref: NC_021314.1); Belliella baltica (NCBI Ref: NC_018010.1); Psychroflexus torquisI (NCBI Ref: NC_018721.1); Streptococcus thermophilus (NCBI Ref: YP_820832.1), Listeria innocua (NCBI Ref: NP_472073.1), Campylobacter jejuni (NCBI Ref: YP_002344900.1); Geobacillus stearothermophilus (NCBI Ref: NZ_CP008934.1); or Neisseria meningitidis (NCBI Ref:

YP_002342100.1) or to a Cas9 from any other organism.

[0073] In some embodiments, a Cas9 domain comprising one or more mutations provided herein is at least about 70% identical, at least about 80% identical, at least about 90% identical, at least about 92%, at least about 95% identical, at least about 98% identical, at least about 99% identical, at least about 99.5% identical, or at least about 99.9% identical to SEQ ID NO: 2. In some embodiments, variants of a Cas9 domain comprising one or more mutations provided herein are provided having amino acid sequences which are shorter, or longer than SEQ ID NO: 2, by about 5 amino acids, by about 10 amino acids, by about 15 amino acids, by about 20 amino acids, by about 25 amino acids, by about 30 amino acids, by about 40 amino acids, by about 50 amino acids, by about 75 amino acids, by about 100 amino acids, or more.

[0074] In some embodiments, the Cas9 domain comprises a D10A mutation, while the residue at position 840 remains a histidine relative to the amino acid sequence as provided in SEQ ID NO: 2, or at corresponding positions in any of the amino acid sequences provided in SEQ ID NO: 2. Without wishing to be bound by any particular theory, the presence of the catalytic residue H840 restores the activity of the Cas9 to cleave the non-edited (e.g., non-deaminated) strand containing a G opposite the targeted C. Restoration of H840 (e.g., from A840) does not result in the cleavage of the target strand containing the C. Such Cas9 variants are able to generate a single-strand DNA break (nick) at a specific location based on the gRNA-defined target sequence, leading to repair of the non-edited strand, ultimately resulting in a base change (e.g., a G to A change) on the non-edited strand. Briefly, the C of a C-G base pair can be deaminated to a U by a deaminase, e.g., an APOBEC deaminase. Nicking the non-edited strand, the strand having the G, facilitates removal of the G via mismatch repair mechanisms. Uracil-DNA glycosylase inhibitor protein (UGI) inhibits Uracil-DNA glycosylase (UDG), which prevents removal of the U.

[0075] In other embodiments, dCas9 variants having mutations other than D10A and H840A are provided, which, e.g., result in nuclease inactivated Cas9 (dCas9). Such mutations, by way of example, include other amino acid substitutions at D10 and H820, or other substitutions within the nuclease domains of Cas9 (e.g., substitutions in the HNH nuclease subdomain and/or the RuvC1 subdomain).

[0076] The term“Cas9 nickase” or“Cas9n” or“nCas9” as used herein, refers to a Cas9 domain that is capable of cleaving one strand of the duplexed nucleic acid molecule (e.g., a duplexed DNA molecule). In some embodiments, a Cas9 nickase comprises a D10A mutation and has a histidine at position H840 of SEQ ID NO: 2, or a corresponding mutation in any of SEQ ID NOs: 2. For example, in some embodiments, a Cas9 nickase comprises the amino acid sequence as set forth in SEQ ID NO: 8 comprising the H840A substitution. Such a Cas9 nickase (Cas9n) has an active HNH nuclease domain and is able to cleave the non-targeted strand of DNA, i.e., the strand bound by the gRNA. Further, such a Cas9 nickase has an inactive RuvC nuclease domain and is not able to cleave the targeted strand of the DNA, i.e., the strand where base editing is desired. In some embodiments, any of the Cas9 domains provided herein comprises a D10A mutation (e.g., SEQ ID NO: 7). In some embodiments, any of the Cas9 domains provided herein comprises a H840A mutation (SEQ ID NO: 8). Exemplary Cas9 nickases are shown below. However, it should be appreciated that additional Cas9 nickases that generate a single-stranded DNA break of a DNA duplex would be apparent to the skilled artisan and are within the scope of this disclosure.

[0077] In some embodiments, Cas9 fusion proteins as provided herein comprise the full-length amino acid sequence of a Cas9 domain, e.g., one of the sequences provided above. In other embodiments, however, fusion proteins as provided herein do not comprise a full-length Cas9 sequence, but only a fragment thereof. For example, in some embodiments, a Cas9 fusion protein provided herein comprises a Cas9 fragment, wherein the fragment binds crRNA and tracrRNA or a sgRNA, but does not comprise a functional nuclease domain, e.g., it comprises only a truncated version of a nuclease domain or no nuclease domain at all. Exemplary amino acid sequences of suitable Cas9 domains and Cas9 fragments are provided herein, and additional suitable sequences of Cas9 domains and Cas9 fragments will be apparent to those of skill in the art. In some embodiments, a Cas9 fragment is at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95% identical, at least 96%, at least 97%, at least 98%, at least 99%, or at least 99.5% of the amino acid length of a corresponding wild type Cas9 domain. In some embodiments, a Cas9 fragment comprises at least at least 100 amino acids in length. In some embodiments, the Cas9 fragment is at least 100, 150, 200, 250, 300, 350, 400, 450, 500, 550, 600, 650, 700, 750, 800, 850, 900, 950, 1000, 1050, 1100, 1150, 1200, 1250, 1300, 1350, 1400, 1450, 1500, 1550, or at least 1600 amino acids of a corresponding wild type Cas9 domain. In some embodiments, the Cas9 fragment comprises an amino acid sequence that has at least 10, at least 15, at least 20, at least 30, at least 40, at least 50, at least 60, at least 70, at least 80, at least 90, at least 100, at least 150, at least 200, at least 250, at least 300, at least 350, at least 400, at least 500, at least 600, at least 700, at least 800, at least 900, at least 1000, at least 1100, or at least 1200 identical contiguous amino acid residues of a corresponding wild type Cas9 domain. In some embodiments, the wild-type protein is S. pyogenes Cas9 (SpCas9) of SEQ ID NO: 2.

[0078] In some embodiments, Cas9 fusion proteins as provided herein comprise the full-length amino acid sequence of a Cas9 domain, e.g., one of the Cas9 sequences provided herein. In other embodiments, however, fusion proteins as provided herein do not comprise a full-length Cas9 sequence, but only a fragment thereof. For example, in some embodiments, a Cas9 fusion protein provided herein comprises a Cas9 fragment, wherein the fragment binds crRNA and tracrRNA or sgRNA, but does not comprise a functional nuclease domain, e.g., in that it comprises only a truncated version of a nuclease domain or no nuclease domain at all. Exemplary amino acid sequences of suitable Cas9 domains and Cas9 fragments are provided herein, and additional suitable sequences of Cas9 domains and fragments will be apparent to those of ordinary skill in the art. In some

embodiments, Cas9 refers to Cas9 from: Corynebacterium ulcerans (NCBI Refs: NC_015683.1, NC_017317.1); Corynebacterium diphtheria (NCBI Refs: NC_016782.1, NC_016786.1);

Spiroplasma syrphidicola (NCBI Ref: NC_021284.1); Prevotella intermedia (NCBI Ref:

NC_017861.1); Spiroplasma taiwanense (NCBI Ref: NC_021846.1); Streptococcus iniae (NCBI Ref: NC_021314.1); Belliella baltica (NCBI Ref: NC_018010.1); Psychroflexus torquis I (NCBI Ref: NC_018721.1); Streptococcus thermophilus (NCBI Ref: YP_820832.1); Geobacillus

stearothermophilus (NCBI Ref: NZ_CP008934.1); Listeria innocua (NCBI Ref: NP_472073.1); Campylobacter jejuni (NCBI Ref: YP_002344900.1); or Neisseria. meningitidis (NCBI Ref:

YP_002342100.1).

[0079] The term“deaminase” or“deaminase domain,” as used herein, refers to a protein or enzyme that catalyzes a deamination reaction. In some embodiments, the deaminase or deaminase domain is a naturally-occurring deaminase from an organism, such as a human, chimpanzee, gorilla, monkey, cow, dog, rat, or mouse. In some embodiments, the deaminase or deaminase domain is a variant of a naturally-occurring deaminase from an organism, that does not occur in nature. For example, in some embodiments, the deaminase or deaminase domain is at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75% at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or at least 99.5% identical to a naturally-occurring deaminase from an organism.

[0080] In some embodiments, the deaminase or deaminase domain is a cytidine deaminase, catalyzing the hydrolytic deamination of cytidine or deoxycytidine to uridine or deoxyuridine, respectively. In some embodiments, the deaminase or deaminase domain is a cytidine deaminase domain, catalyzing the hydrolytic deamination of cytosine to uracil. In some embodiments, the cytidine deaminase catalyzes the hydrolytic deamination of cytidine or cytosine in deoxyribonucleic acid (DNA). In some embodiments, the cytidine deaminase domain comprises the amino acid sequence of any one disclosed herein. In some embodiments, the cytidine deaminase or cytidine deaminase domain is a naturally-occurring cytidine deaminase from an organism, such as a human, chimpanzee, gorilla, monkey, cow, dog, rat, or mouse. In some embodiments, the cytidine deaminase or cytidine deaminase domain is a variant of a naturally-occurring cytidine deaminase from an organism that does not occur in nature. For example, in some embodiments, the cytidine deaminase or cytidine deaminase domain is at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75% at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or at least 99.5% identical to a naturally-occurring cytidine deaminase from an organism, such as a human, chimpanzee, gorilla, monkey, cow, dog, rat, or mouse.

[0081] In some embodiments, the deaminase or deaminase domain is an adenosine deaminase, which catalyzes the hydrolytic deamination of adenine or adenosine. In some embodiments, the deaminase or deaminase domain is an adenosine deaminase, catalyzing the hydrolytic deamination of adenosine or deoxyadenosine to inosine or deoxyinosine, respectively. In some embodiments, the adenosine deaminase catalyzes the hydrolytic deamination of adenine or adenosine in

deoxyribonucleic acid (DNA). The adenosine deaminases (e.g., engineered adenosine deaminases, evolved adenosine deaminases) provided herein may be from any organism, such as a bacterium. In some embodiments, the deaminase or deaminase domain is a variant of a naturally-occurring deaminase from an organism. In some embodiments, the deaminase or deaminase domain does not occur in nature. For example, in some embodiments, the deaminase or deaminase domain is at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75% at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or at least 99.5% identical to a naturally-occurring deaminase. In some embodiments, the adenosine deaminase is from a bacterium, such as E.coli, S. aureus, S. typhi, S. putrefaciens, H. influenzae, or C. crescentus. In some embodiments, the adenosine deaminase is a TadA deaminase. In some embodiments, the TadA deaminase is an E. coli TadA deaminase (ecTadA). In some embodiments, the TadA deaminase is a truncated E. coli TadA deaminase. For example, the truncated ecTadA may be missing one or more N- terminal amino acids relative to a full-length ecTadA. In some embodiments, the truncated ecTadA may be missing 1, 2, 3, 4, 5 ,6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 6, 17, 18, 19, or 20 N-terminal amino acid residues relative to the full length ecTadA. In some embodiments, the truncated ecTadA may be missing 1, 2, 3, 4, 5 ,6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 6, 17, 18, 19, or 20 C-terminal amino acid residues relative to the full length ecTadA. In some embodiments, the ecTadA deaminase does not comprise an N-terminal methionine.

[0082] In some embodiments, the TadA deaminase is an N-terminal truncated TadA. In certain embodiments, the adenosine deaminase comprises the amino acid sequence:

[0083] In some embodiments the TadA deaminase is a full-length E. coli TadA deaminase. For example, in certain embodiments, the adenosine deaminase comprises the amino acid sequence:

[0084] It should be appreciated, however, that additional adenosine deaminases useful in the present application would be apparent to the skilled artisan and are within the scope of this disclosure. For example, the adenosine deaminase may be a homolog of an ADAT. Exemplary ADAT homologs include, without limitation:

[0085] The term“effective amount,” as used herein, refers to an amount of a biologically active agent that is sufficient to elicit a desired biological response. For example, in some embodiments, an effective amount of a nuclease may refer to the amount of the nuclease that is sufficient to induce cleavage of a target site specifically bound and cleaved by the nuclease. In some embodiments, an effective amount of a fusion protein provided herein, e.g., of a fusion protein comprising a Cas9 domain and a nucleic acid editing domain (e.g., a deaminase domain) may refer to the amount of the fusion protein that is sufficient to induce editing of a target site specifically bound and edited by the fusion protein. As will be appreciated by the skilled artisan, the effective amount of an agent, e.g., a fusion protein, a nuclease, a deaminase, a recombinase, a hybrid protein, a protein dimer, a complex of a protein (or protein dimer) and a polynucleotide, or a polynucleotide, may vary depending on various factors such as, for example, on the desired biological response, e.g., on the specific allele, genome, or target site to be edited; on the cell or tissue being targeted; and on the agent (e.g., Cas9 domain, fusion protein, vector, cell, etc.) being used.

[0086] The term“immediately adjacent” as used in the context of two nucleic acid sequences refers to two sequences that directly abut each other as part of the same nucleic acid molecule and are not separated by one or more nucleotides. Accordingly, sequences are immediately adjacent, when the nucleotide at the 3ʹ-end of one of the sequences is directly connected to nucleotide at the 5ʹ-end of the other sequence via a phosphodiester bond.

[0087] The term“linker,” as used herein, refers to a chemical group or a molecule linking two molecules or moieties, e.g., two domains of a fusion protein, such as, for example, a nuclease-inactive Cas9 domain and a nucleic acid editing domain (e.g., a deaminase domain). A linker may be, for example, an amino acid sequence, a peptide, or a polymer of any length and composition. In some embodiments, a linker joins a gRNA binding domain of an RNA-programmable nuclease, including a Cas9 nuclease domain, and the catalytic domain of a nucleic-acid editing protein. In some embodiments, a linker joins a dCas9 and a nucleic-acid editing protein. In some embodiments, a linker joins a Cas9n and a nucleic-acid editing protein. In some embodiments, a linker joins an RNA- programmable nuclease domain and a UGI domain. In some embodiments, a linker joins a dCas9 and a UGI domain. In some embodiments, a linker joins a Cas9n and a UGI domain. Typically, the linker is positioned between, or flanked by, two groups, molecules, or other moieties and connected to each one via a covalent bond, thus connecting the two. In some embodiments, the linker is an amino acid or a plurality of amino acids (e.g., a peptide or protein). In some embodiments, the linker is an organic molecule, group, polymer, or chemical moiety. In some embodiments, the linker is 1-100 amino acids in length, for example, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 30-35, 35-40, 40-45, 45-50, 50-60, 60-70, 70-80, 80-90, 90-100, 100-150, or 150-200 amino acids in length. Longer or shorter linkers are also contemplated. In some

embodiments, a linker comprises the amino acid sequence SGSETPGTSESATPES (SEQ ID NO: 89), which may also be referred to as the XTEN linker. In some embodiments, a linker comprises the amino acid sequence SGGS (SEQ ID NO: 90). In some embodiments, a linker comprises the amino acid sequence (SGGS)2-SGSETPGTSESATPES-(SGGS)2 (SEQ ID NO: 96), which may also be referred to as (SGGS)2-XTEN-(SGGS)2. In some embodiments, a linker comprises (SGGS)n (SEQ ID NO: 92), (GGGS)n (SEQ ID NO: 94), (GGGGS)n (SEQ ID NO: 96), (G)n (SEQ ID NO: 97), (EAAAK)n (SEQ ID NO: 99), (GGS)n (SEQ ID NO: 101), SGGS(GGS)n (SEQ ID NO: 103), (SGGS)n-SGSETPGTSESATPES-(SGGS)n (SEQ ID NO: 98), or (XP)n motif, or a combination of any of these, wherein n is independently an integer between 1 and 30, and wherein X is any amino acid. In some embodiments, n is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15. In some

embodiments, n is 1, 3, or 7. In some embodiments, the linker comprises the amino acid sequence:

[0088] The term“mutation,” as used herein, refers to a substitution of a residue within a sequence, e.g., a nucleic acid or amino acid sequence, with another residue, or a deletion or insertion of one or more residues within a sequence. Mutations are typically described herein by identifying the original residue followed by the position of the residue within the sequence and by the identity of the newly substituted residue. Various methods for making the amino acid substitutions (mutations) provided herein are well known in the art, and are provided by, for example, Green and Sambrook, Molecular Cloning: A Laboratory Manual (4 ^th ed., Cold Spring Harbor Laboratory Press, Cold Spring Harbor, N.Y. (2012)).

[0089] The terms“nucleic acid” and“nucleic acid molecule,” as used herein, refer to a compound comprising a nucleobase and an acidic moiety, e.g., a nucleoside, a nucleotide, or a polymer of nucleotides. Typically, polymeric nucleic acids, e.g., nucleic acid molecules comprising three or more nucleotides are linear molecules, in which adjacent nucleotides are linked to each other via a phosphodiester linkage. In some embodiments,“nucleic acid” refers to individual nucleic acid residues (e.g. nucleotides and/or nucleosides). In some embodiments,“nucleic acid” refers to an oligonucleotide chain comprising three or more individual nucleotide residues. As used herein, the terms“oligonucleotide” and“polynucleotide” can be used interchangeably to refer to a polymer of nucleotides (e.g., a string of at least three nucleotides). In some embodiments,“nucleic acid” encompasses RNA as well as single and/or double-stranded DNA. Nucleic acids may be naturally occurring, for example, in the context of a genome, a transcript, mRNA, tRNA, rRNA, siRNA, snRNA, a plasmid, cosmid, chromosome, chromatid, or other naturally occurring nucleic acid molecule. On the other hand, a nucleic acid molecule may be a non-naturally occurring molecule, e.g., a DNA or RNA, an artificial chromosome, an engineered genome, or fragment thereof, or a synthetic DNA, RNA, DNA/RNA hybrid, or including non-naturally occurring nucleotides or nucleosides. Furthermore, the terms“nucleic acid,”“DNA,”“RNA,” and/or similar terms include nucleic acid analogs, e.g., analogs having other than a phosphodiester backbone. Nucleic acids can be purified from natural sources, produced using expression systems and optionally purified, chemically synthesized, etc. Where appropriate, e.g., in the case of chemically synthesized molecules, nucleic acids can comprise nucleoside analogs such as analogs having chemically modified bases or sugars, and backbone modifications. A nucleic acid sequence is presented in the 5¢ to 3¢ direction unless otherwise indicated. In some embodiments, a nucleic acid is or comprises natural nucleosides (e.g. adenosine, thymidine, guanosine, cytidine, uridine, deoxyadenosine, deoxythymidine, deoxyguanosine, and deoxycytidine); nucleoside analogs (e.g., 2-aminoadenosine, 2-thiothymidine, inosine, pyrrolo-pyrimidine, 3-methyl adenosine, 5-methylcytidine, 2-aminoadenosine, C5- bromouridine, C5-fluorouridine, C5-iodouridine, C5-propynyl-uridine, C5-propynyl-cytidine, C5- methylcytidine, 2-aminoadenosine, 7-deazaadenosine, 7-deazaguanosine, 8-oxoadenosine, 8- oxoguanosine, O(6)-methylguanine, and 2-thiocytidine); chemically modified bases; biologically modified bases (e.g., methylated bases); intercalated bases; modified sugars (e.g., 2¢-fluororibose, ribose, 2¢-deoxyribose, arabinose, and hexose); and/or modified phosphate groups (e.g.,

phosphorothioates and 5¢-N-phosphoramidite linkages). In some embodiments, an RNA is an RNA associated with the Cas9 system. For example, the RNA may be a CRISPR RNA (crRNA), a trans- encoded small RNA (tracrRNA), a single guide RNA (sgRNA), or a guide RNA (gRNA).

[0090] The term“nucleic acid editing domain,” as used herein refers to a protein or enzyme capable of making one or more modifications (e.g., deamination of a cytidine residue) to a nucleic acid (e.g., DNA or RNA). Exemplary nucleic acid editing domains include, but are not limited to a deaminase, a nuclease, a nickase, a recombinase, a methyltransferase, a methylase, an acetylase, an

acetyltransferase, a transcriptional activator, or a transcriptional repressor domain. In some embodiments, the nucleic acid editing domain is a deaminase, a nuclease, a nickase, a recombinase, a methyltransferase, a methylase, an acetylase, an acetyltransferase, a transcriptional activator, or a transcriptional repressor domain. In some embodiments, the nucleic acid editing domain is a deaminase domain (e.g., a cytidine deaminase, such as an APOBEC or an AID deaminase, or an adenosine deaminase, such as ecTadA). In some embodiments, the nucleic acid editing domain is a cytidine deaminase domain (e.g., an APOBEC or an AID deaminase). In some embodiments, the nucleic acid editing domain is an adenosine deaminase domain (e.g., an ecTadA).

[0091] The term“nuclear localization sequence” or“NLS” refers to an amino acid sequence that promotes import of a protein into the cell nucleus, for example, by nuclear transport. Nuclear localization sequences are known in the art and would be apparent to the skilled artisan. For example, NLS sequences are described in Plank et al., international PCT application, PCT/EP2000/011690, filed November 23, 2000, published as WO/2001/038547 on May 31, 2001, the contents of which are incorporated herein by reference for its disclosure of exemplary nuclear localization sequences. In some embodiments, a NLS comprises the amino acid sequence PKKKRKV (SEQ ID NO: 113) or MDSLLMNRRKFLYQFKNVRWAKGRRETYLC (SEQ ID NO: 114).

[0092] The term“proliferative disease,” as used herein, refers to any disease in which cell or tissue homeostasis is disturbed in that a cell or cell population exhibits an abnormally elevated proliferation rate. Proliferative diseases include hyperproliferative diseases, such as pre-neoplastic hyperplastic conditions and neoplastic diseases. Neoplastic diseases are characterized by an abnormal proliferation of cells and include both benign and malignant neoplasias. Malignant neoplasia is also referred to as cancer.

[0093] The terms“protein,”“peptide,” and“polypeptide” are used interchangeably herein, and refer to a polymer of amino acid residues linked together by peptide (amide) bonds. The terms refer to a protein, peptide, or polypeptide of any size, structure, or function. Typically, a protein, peptide, or polypeptide will be at least three amino acids long. A protein, peptide, or polypeptide may refer to an individual protein or a collection of proteins. One or more of the amino acids in a protein, peptide, or polypeptide may be modified, for example, by the addition of a chemical entity such as a

carbohydrate group, a hydroxyl group, a phosphate group, a farnesyl group, an isofarnesyl group, a fatty acid group, a linker for conjugation, functionalization, or other modification, etc. A protein, peptide, or polypeptide may also be a single molecule or may be a multi-molecular complex. A protein, peptide, or polypeptide may be just a fragment of a naturally occurring protein or peptide. A protein, peptide, or polypeptide may be naturally occurring, or synthetic, or any combination thereof. The term“fusion protein” as used herein refers to a hybrid polypeptide which comprises protein domains from at least two different proteins, or at least two identical protein domains (i.e., a homodimer). One protein may be located at the amino-terminal (N-terminal) portion of the fusion protein or at the carboxy-terminal (C-terminal) protein thus forming an“amino-terminal fusion protein” or a“carboxy-terminal fusion protein,” respectively. A protein may comprise different domains, for example, a nucleic acid binding domain (e.g., the gRNA binding domain of Cas9 that directs the binding of the protein to a target site) and a nucleic acid cleavage domain or a catalytic domain of a nucleic acid editing protein. In some embodiments, a protein comprises a proteinaceous part, e.g., an amino acid sequence constituting a nucleic acid binding domain, and an organic compound, e.g., a compound that can act as a nucleic acid cleavage agent. In some embodiments, a protein is in a complex with, or is in association with, a nucleic acid, e.g., RNA. Any of the proteins provided herein may be produced by any method known in the art. For example, the proteins provided herein may be produced via protein expression and purification, which is especially suited for fusion proteins comprising a peptide linker. Methods for protein expression and purification are well known, and include those described by Green and Sambrook, Molecular Cloning: A Laboratory Manual (4 ^th ed., Cold Spring Harbor Laboratory Press, Cold Spring Harbor, N.Y. (2012)), the entire contents of which are incorporated herein by reference.

[0094] The term“subject,” as used herein, refers to an individual organism, for example, an individual mammal. In some embodiments, the subject is a human. In some embodiments, the subject is a non-human mammal. In some embodiments, the subject is a non-human primate. In some embodiments, the subject is a rodent. In some embodiments, the subject is a sheep, a goat, a cattle, a cat, or a dog. In some embodiments, the subject is a vertebrate, an amphibian, a reptile, a fish, an insect, a fly, or a nematode. In some embodiments, the subject is a plant or a fungus. In some embodiments, the subject is a research animal (e.g., a rat, a mouse, or a non-human primate). In some embodiments, the subject is genetically engineered, e.g., a genetically engineered non-human subject. The subject may be of either sex, of any age, and at any stage of development.

[0095] The term“target site” refers to a nucleic acid sequence or a nucleotide within a nucleic acid that is targeted or modified by an effector domain that is fused to a napDNAbp. In some embodiments, a“target site” is a sequence within a nucleic acid molecule that is deaminated by a deaminase or a fusion protein comprising a deaminase, (e.g., a dCas9-deaminase fusion protein or a Cas9n-deaminase fusion protein provided herein). In some embodiments, the target site refers to a sequence within a nucleic acid molecule that is cleaved by a napDNAbp (e.g., a nuclease active Cas9 domain) provided herein. The target site is contained within a target sequence (e.g., a target sequence comprising a reporter gene, or a target sequence comprising a gene located in a safe harbor locus).

[0096] The terms“treatment,”“treat,” and“treating,” refer to a clinical intervention aimed to reverse, alleviate, delay the onset of, or inhibit the progress of a disease or disorder, or one or more symptoms thereof, as described herein. As used herein, the terms“treatment,”“treat,” and“treating” refer to a clinical intervention aimed to reverse, alleviate, delay the onset of, or inhibit the progress of a disease or disorder, or one or more symptoms thereof, as described herein. In some embodiments, treatment may be administered after one or more symptoms have developed and/or after a disease has been diagnosed. In other embodiments, treatment may be administered in the absence of symptoms, e.g., to prevent or delay onset of a symptom or inhibit onset or progression of a disease. For example, treatment may be administered to a susceptible individual prior to the onset of symptoms (e.g., in light of a history of symptoms and/or in light of genetic or other susceptibility factors). Treatment may also be continued after symptoms have resolved, for example, to prevent or delay their recurrence.

[0097] The term“pharmaceutical composition,” as used herein, refers to a composition that can be administrated to a subject in the context of treatment of a disease or disorder. In some embodiments, a pharmaceutical composition comprises an active ingredient, e.g., a nuclease or a nucleic acid encoding a nuclease, and a pharmaceutically acceptable excipient.

[0098] The term“uracil glycosylase inhibitor” or“UGI,” as used herein, refers to a protein that is capable of inhibiting a uracil-DNA glycosylase base-excision repair enzyme. In some embodiments, a UGI domain comprises a wild-type UGI or a UGI as set forth in SEQ ID NO: 115-120. In some embodiments, the UGI proteins provided herein include fragments of UGI and proteins homologous to a UGI or a UGI fragment. For example, in some embodiments, a UGI domain comprises a fragment of the amino acid sequence set forth in SEQ ID NO: 115-120. In some embodiments, a UGI fragment comprises an amino acid sequence that comprises at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or at least 99.5% of the amino acid sequence as set forth in SEQ ID NO: 115-120. In some embodiments, a UGI comprises an amino acid sequence homologous to the amino acid sequence set forth in SEQ ID NO: 115-120, or an amino acid sequence homologous to a fragment of the amino acid sequence set forth in SEQ ID NO: 115-120. In some embodiments, proteins comprising UGI or fragments of UGI or homologs of UGI or UGI fragments are referred to as“UGI variants.” A UGI variant shares homology to UGI, or a fragment thereof. For example a UGI variant is at least 70% identical, at least 75% identical, at least 80% identical, at least 85% identical, at least 90% identical, at least 95% identical, at least 96% identical, at least 97% identical, at least 98% identical, at least 99% identical, at least 99.5% identical, or at least 99.9% identical to a wild type UGI or a UGI as set forth in SEQ ID NO: 115-120. In some embodiments, the UGI variant comprises a fragment of UGI, such that the fragment is at least 70% identical, at least 80% identical, at least 90% identical, at least 95% identical, at least 96% identical, at least 97% identical, at least 98% identical, at least 99% identical, at least 99.5% identical, or at least 99.9% to the corresponding fragment of wild- type UGI or a UGI as set forth in SEQ ID NO: 115-120. In some embodiments, the UGI comprises the amino acid sequence of SEQ ID NO: 115, as set forth below. Exemplary Uracil-DNA glycosylase inhibitor (UGI; >sp|P14739|UNGI_BPPB2)

MTNLSDIIEKETGKQLVIQESILMLPEEVEEVIGNKPESDILVHTAYDESTDENVML LTSDAPEYKPW ALVIQDSNGENKIKML (SEQ ID NO: 115).

[0099] The term“catalytically inactive inosine-specific nuclease,” or“dead inosine-specific nuclease (dISN),” as used herein, refers to a protein that is capable of inhibiting an inosine-specific nuclease. Without wishing to be bound by any particular theory, catalytically inactive inosine glycosylases (e.g., alkyl adenine glycosylase [AAG]) will bind inosine, but will not create an abasic site or remove the inosine, thereby sterically blocking the newly-formed inosine moiety from DNA damage/repair mechanisms. In some embodiments, the catalytically inactive inosine-specific nuclease may be capable of binding an inosine in a nucleic acid but does not cleave the nucleic acid.

Exemplary catalytically inactive inosine-specific nucleases include, without limitation, catalytically inactive alkyl adenosine glycosylase (AAG nuclease), for example, from a human, and catalytically inactive endonuclease V (EndoV nuclease), for example, from E. coli. In some embodiments, the catalytically inactive AAG nuclease comprises an E125Q mutation as shown in SEQ ID NO: 40, or a corresponding mutation in another AAG nuclease. In some embodiments, the catalytically inactive AAG nuclease comprises the amino acid sequence set forth in SEQ ID NO: 40. In some

embodiments, the catalytically inactive EndoV nuclease comprises an D35A mutation as shown in SEQ ID NO: 41, or a corresponding mutation in another EndoV nuclease. In some embodiments, the catalytically inactive EndoV nuclease comprises the amino acid sequence set forth in SEQ ID NO: 41. It should be appreciated that other catalytically inactive inosine-specific nucleases (dISNs) would be apparent to the skilled artisan and are within the scope of this disclosure. Various examples include:

Truncated AAG (H. sapiens) nuclease (E125Q); mutated residue shown in bold. KGHLTRLGLEFFDQPAVPLARAFLGQVLVRRLPNGTELRGRIVETQAYLGPEDEAAHSRG GRQTPRNR GMFMKPGTLYVYIIYGMYFCMNISSQGDGACVLLRALEPLEGLETMRQLRSTLRKGTASR VLKDRELC SGPSKLCQALAINKSFDQRDLAQDEAVWLERGPLEPSEPAVVAAARVGVGHAGEWARKPL RFYVRGSP WVSVVDRVAEQDTQA (SEQ ID NO: 116); and

EndoV nuclease (D35A); mutated residue shown in bold.

DLASLRAQQIELASSVIREDRLDKDPPDLIAGAAVGFEQGGEVTRAAMVLLKYPSLE LVEYKVARIAT TMPYIPGFLSFREYPALLAAWEMLSQKPDLVFVDGHGISHPRRLGVASHFGLLVDVPTIG VAKKRLCG KFEPLSSEPGALAPLMDKGEQLAWVWRSKARCNPLFIATGHRVSVDSALAWVQRCMKGYR LPEPTRWA DAVASERPAFVRYTANQP (SEQ ID NO: 117). DETAILED DESCRIPTION OF CERTAIN EMBODIMENTS

[00100] Streptococcus pyogenes Cas9 (SpCas9) is a widely-utilized genome-editing tool, but is restricted in genome targeting by the requirement for an NGG PAM sequence, which can be limiting for precision genome editing applications such as base editing, homology-directed repair, and predictable template-free genome editing. While SpCas9 variants with alternative PAM requirements have been previously reported, their targeting scope remains restricted primarily to G-containing PAMs.

[00101] The present application provides three SpCas9 variants capable of recognizing NRTH, NRRH, and NRCH PAMs, respectively, using an improved phage-assisted continuous evolution (PACE) Cas9 binding selection. These PAM sequence preferences are provided for these SpCas9 variants, along with the previously reported SpCas9-NG variant, by cytosine base editing, indel formation, and adenine base editing in a panel of 64 mammalian potential cell target sites. In further aspects, the present application provides the editing efficiencies of the SpCas9 variants on a mammalian cell library of ~12,000 genomically integrated sgRNA/protospacer targets.

[00102] Some aspects of this disclosure provide Cas9 proteins (e.g., SgCas9) that efficiently target nucleic acid sequences that do not include the canonical PAM sequence (5´-NGG-3´, where N is any nucleotide, for example A, T, G, or C) at their 3’-ends. It should be appreciated that the phrase“Cas9 proteins” can refer to isolated Cas9 proteins or Cas9 domains as part of fusion proteins. In some embodiments, the Cas9 domains provided herein comprise one or more mutations identified in directed evolution experiments using a target sequence library comprising randomized PAM sequences. The non-PAM restricted Cas9 domains provided herein are useful for targeting DNA sequences that do not comprise the canonical PAM sequence at their 3’-end and thus greatly extend the applicability and usefulness of Cas9 technology for gene editing. The evolution of Cas9 domains that are not restricted to the canonical 5´-NGG-3´ PAM sequence has been previously described, for example, in International Patent Application No., PCT/US2016/058345, filed October 22, 2016, and published as Patent Publication No. WO 2017/070633, published April 27, 2017, entitled“Evolved Cas9 Proteins for Gene Editing” which is herein incorporated by reference in its entirety. In addition to the Cas9 mutations identified and proteins listed in Publication No. WO 2017/070633, provided herein are novel additional mutations and Cas9 domains that have activity on target sequences comprising non-canonical PAM sequences. It should be understood that any of the mutations listed in Patent Publication No. WO 2017/070633 may be combined with or used in lieu of any of the mutations or Cas9 domains disclosed herein, unless explicity stated otherwise.

[00103] Some aspects of this disclosure provide fusion proteins that comprise a Cas9 domain and an effector domain, for example, a nucleic acid editing domain, such as a deaminase domain, a nuclease domain, a nickase domain, a recombinase domain, a methyltransferase domain, a methylase domain, an acetylase domain, an acetyltransferase domain, a transcriptional activator domain, or a transcriptional repressor domain.

[00104] The deamination of a nucleobase by a deaminase can lead to a point mutation at the specific residue, which is referred to herein as nucleic acid editing. Fusion proteins comprising a Cas9 domain or variant thereof and a nucleic acid editing domain can thus be used for the targeted editing of nucleic acid sequences. Such fusion proteins are useful for targeted editing of DNA in vitro, e.g., for the generation of mutant cells or animals; for the introduction of targeted mutations, e.g., for the correction of genetic defects in cells ex vivo, e.g., in cells obtained from a subject that are subsequently re-introduced into the same or another subject; and for the introduction of targeted mutations, e.g., the correction of genetic defects or the introduction of deactivating mutations in disease-associated genes in a subject in vivo. Typically, the Cas9 domain of the fusion proteins described herein is a Cas9 domain comprising one or more mutations provided herein (e.g., an “xCas9” domain) that has impaired nuclease activity (e.g., a nuclease-inactive xCas9 domain). For example, in some embodiments, the Cas9 domain comprises a D10A and/or a H840A mutation in the amino acid sequence provided in SEQ ID NO: 2. Methods for the use of fusion proteins comprising Cas9 as described herein are also provided.

[00105] Additional suitable nuclease-inactive Cas9 domains will be apparent to those of skill in the art based on this disclosure. Such additional exemplary suitable nuclease-inactive Cas9 domains include, but are not limited to, D10A, D839A, H840A, N863A, D10A/D839A, D10A/H840A, D10A/N863A, D839A/H840A, D839A/N863A, D10A/D839A/H840A, and

D10A/D839A/H840A/N863A mutant proteins (See, e.g., Prashant et al.,“Cas9 transcriptional activators for target specificity screening and paired nickases for cooperative genome engineering,” Nature Biotechnology, 2013; 31(9): 833-838, the entire contents of which are incorporated herein by reference). In some embodiments, the Cas9 domain comprises a D10A mutation of the amino acid sequence provided in SEQ ID NO: 2, or a corresponding mutation in any of the amino acid sequences provided in SEQ ID NOs: 2.

[00106] The base editors disclosed herein may also comprise a circular permutant Cas9 variant. The term“circularly permuted Cas9” refers to any Cas9 protein, or variant thereof, that occurs or has been modify to occur as a circular permutant, whereby its N- and C-termini have been topically rearranged. Such circularly permuted Cas9 proteins (“CP-Cas9”), or variants thereof, retain the ability to bind DNA when complexed with a guide RNA (gRNA). See, Oakes et al.,“Protein Engineering of Cas9 for enhanced function,” Methods Enzymol, 2014, 546: 491–511 and Oakes et al., “CRISPR-Cas9 Circular Permutants as Programmable Scaffolds for Genome Modification,” Cell, January 10, 2019, 176: 254-267, each of are incorporated herein by reference. The instant disclosure contemplates any previously known CP-Cas9 or use a new CP-Cas9 so long as the resulting circularly permuted protein retains the ability to bind DNA when complexed with a guide RNA (gRNA).

[00107] Any of the Cas9 proteins described herein, including any variant, ortholog, or naturally occurring Cas9 or equivalent thereof, may be reconfigured as a circular permutant variant.

[00108] In various embodiments, the circular permutants of Cas9 may have the following structure: N-terminus-[original C-terminus]– [optional linker]– [original N-terminus]-C-terminus.

[00109] As an example, the present disclosure contemplates the following circular permutants of S. pyogenes Cas9 (based on 1368 amino acids of UniProtKB - Q99ZW2 (CAS9_STRP1) of SEQ ID NO: 6:

[00110] N-terminus-[1268-1368]-[optional linker]-[1-1267]-C-terminus;

[00111] N-terminus-[1168-1368]-[optional linker]-[1-1167]-C-terminus;

[00112] N-terminus-[1068-1368]-[optional linker]-[1-1067]-C-terminus;

[00113] N-terminus-[968-1368]-[optional linker]-[1-967]-C-terminus;

[00114] N-terminus-[868-1368]-[optional linker]-[1-867]-C-terminus;

[00115] N-terminus-[768-1368]-[optional linker]-[1-767]-C-terminus;

[00116] N-terminus-[668-1368]-[optional linker]-[1-667]-C-terminus;

[00117] N-terminus-[568-1368]-[optional linker]-[1-567]-C-terminus;

[00118] N-terminus-[468-1368]-[optional linker]-[1-467]-C-terminus;

[00119] N-terminus-[368-1368]-[optional linker]-[1-367]-C-terminus;

[00120] N-terminus-[268-1368]-[optional linker]-[1-267]-C-terminus;

[00121] N-terminus-[168-1368]-[optional linker]-[1-167]-C-terminus;

[00122] N-terminus-[68-1368]-[optional linker]-[1-67]-C-terminus; or

[00123] N-terminus-[10-1368]-[optional linker]-[1-9]-C-terminus, or the corresponding circular permutants of other Cas9 proteins (including other Cas9 orthologs, variants, etc). [00124] In particular embodiments, the circular permuant Cas9 has the following structure (based on S. pyogenes Cas9 (SEQ ID NO: 6):

[00125] N-terminus-[102-1368]-[optional linker]-[1-101]-C-terminus;

[00126] N-terminus-[1028-1368]-[optional linker]-[1-1027]-C-terminus;

[00127] N-terminus-[1041-1368]-[optional linker]-[1-1043]-C-terminus;

[00128] N-terminus-[1249-1368]-[optional linker]-[1-1248]-C-terminus; or

[00129] N-terminus-[1300-1368]-[optional linker]-[1-1299]-C-terminus, or the corresponding circular permutants of other Cas9 proteins (including other Cas9 orthologs, variants, etc).

[00130] In still other embodiments, the circular permutant Cas9 has the following structure (based on S. pyogenes Cas9 (SEQ ID NO: 6):

[00131] N-terminus-[103-1368]-[optional linker]-[1-102]-C-terminus;

[00132] N-terminus-[1029-1368]-[optional linker]-[1-1028]-C-terminus;

[00133] N-terminus-[1042-1368]-[optional linker]-[1-1041]-C-terminus;

[00134] N-terminus-[1250-1368]-[optional linker]-[1-1249]-C-terminus; or

[00135] N-terminus-[1301-1368]-[optional linker]-[1-1300]-C-terminus, or the corresponding circular permutants of other Cas9 proteins (including other Cas9 orthologs, variants, etc).

[00136] In some embodiments, the Cas9 variant comprises a fragment of Cas9 (e.g., a gRNA binding domain or a DNA-cleavage domain), such that the fragment is at least about 70% identical, at least about 80% identical, at least about 90% identical, at least about 95% identical, at least about 96% identical, at least about 97% identical, at least about 98% identical, at least about 99% identical, at least about 99.5% identical, or at least about 99.9% identical to the corresponding fragment of wild type Cas9. In some embodiments, the fragment is is at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95% identical, at least 96%, at least 97%, at least 98%, at least 99%, or at least 99.5% of the amino acid length of a corresponding wild type Cas9. In some embodiments, the Cas9 fragment is at least 100 amino acids in length. In some embodiments, the fragment is at least 100, 150, 200, 250, 300, 350, 400, 450, 500, 550, 600, 650, 700, 750, 800, 850, 900, 950, 1000, 1050, 1100, 1150, 1200, 1250, or at least 1300 amino acids in length. In some embodiments, the fragment binds crRNA and tracrRNA or sgRNA, but does not comprise a functional nuclease domain, e.g., in that it comprises only a truncated version of a nuclease domain or no nuclease domain at all.

[00137] In some embodiments, the circular permutant can be formed by linking a C-terminal fragment of a Cas9 to an N-terminal fragment of a Cas9, either directly or by using a linker, such as an amino acid linker. In some embodiments, The C-terminal fragment may correspond to the C- terminal 95% or more of the amino acids of a Cas9 (e.g., amino acids about 1300-1368), or the C- terminal 90%, 85%, 80%, 75%, 70%, 65%, 60%, 55%, 50%, 45%, 40%, 35%, 30%, 25%, 20%, 15%, 10%, or 5% or more of a Cas9 (e.g., SEQ ID NO: 6). The N-terminal portion may correspond to the N-terminal 95% or more of the amino acids of a Cas9 (e.g., amino acids about 1-1300), or the N- terminal 90%, 85%, 80%, 75%, 70%, 65%, 60%, 55%, 50%, 45%, 40%, 35%, 30%, 25%, 20%, 15%, 10%, or 5% or more of a Cas9 (e.g., of SEQ ID NO: 6).

[00138] In some embodiments, the circular permutant can be formed by linking a C-terminal fragment of a Cas9 to an N-terminal fragment of a Cas9, either directly or by using a linker, such as an amino acid linker. In some embodiments, the C-terminal fragment that is rearranged to the N- terminus, includes or corresponds to the C-terminal 30% or less of the amino acids of a Cas9 (e.g., amino acids 1012-1368 of SEQ ID NO: 6). In some embodiments, the C-terminal fragment that is rearranged to the N-terminus, includes or corresponds to the C-terminal 30%, 29%, 28%, 27%, 26%, 25%, 24%, 23%, 22%, 21%, 20%, 19%, 18%, 17%, 16%, 15%, 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, or 1% of the amino acids of a Cas9 (e.g., the Cas9 of SEQ ID NO: 6). In some embodiments, the C-terminal fragment that is rearranged to the N-terminus, includes or corresponds to the C-terminal 410 residues or less of a Cas9 (e.g., the Cas9 of SEQ ID NO: 6). In some embodiments, the C-terminal portion that is rearranged to the N-terminus, includes or corresponds to the C-terminal 410, 400, 390, 380, 370, 360, 350, 340, 330, 320, 310, 300, 290, 280, 270, 260, 250, 240, 230, 220, 210, 200, 190, 180, 170, 160, 150, 140, 130, 120, 110, 100, 90, 80, 70, 60, 50, 40, 30, 20, or 10 residues of a Cas9 (e.g., the Cas9 of SEQ ID NO: 6). In some

embodiments, the C-terminal portion that is rearranged to the N-terminus, includes or corresponds to the C-terminal 357, 341, 328, 120, or 69 residues of a Cas9 (e.g., the Cas9 of SEQ ID NO: 6).

[00139] In other embodiments, circular permutant Cas9 variants may be defined as a topological rearrangement of a Cas9 primary structure based on the following method, which is based on S. pyogenes Cas9 of SEQ ID NO: 6: (a) selecting a circular permutant (CP) site corresponding to an internal amino acid residue of the Cas9 primary structure, which dissects the original protein into two halves: an N-terminal region and a C-terminal region; (b) modifying the Cas9 protein sequence (e.g., by genetic engineering techniques) by moving the original C-terminal region (comprising the CP site amino acid) to preceed the original N-terminal region, thereby forming a new N-terminus of the Cas9 protein that now begins with the CP site amino acid residue. The CP site can be located in any domain of the Cas9 protein, including, for example, the helical-II domain, the RuvCIII domain, or the CTD domain. For example, the CP site may be located (relative to the S. pyogenes Cas9 of SEQ ID NO: 6) at original amino acid residue 181, 199, 230, 270, 310, 1010, 1016, 1023, 1029, 1041, 1247, 1249, or 1282. Thus, once relocated to the N-terminus, original amino acid 181, 199, 230, 270, 310, 1010, 1016, 1023, 1029, 1041, 1247, 1249, or 1282 would become the new N-terminal amino acid. Nomenclature of these CP-Cas9 proteins may be referred to as Cas9-CP ¹⁸¹ , Cas9-CP ¹⁹⁹ , Cas9-CP ²³⁰ , Cas9-CP ²⁷⁰ , Cas9-CP ³¹⁰ , Cas9-CP ¹⁰¹⁰ , Cas9-CP ¹⁰¹⁶ , Cas9-CP ¹⁰²³ , Cas9-CP ¹⁰²⁹ , Cas9-CP ¹⁰⁴¹ , Cas9- CP ¹²⁴⁷ , Cas9-CP ¹²⁴⁹ , and Cas9-CP ¹²⁸² , respectively. This description is not meant to be limited to making CP variants from SEQ ID NO: 6, but may be implemented to make CP variants in any Cas9 sequence, either at CP sites that correspond to these positions, or at other CP sites entirely. This description is not meant to limit the specific CP sites in any way. Virtually any CP site may be used to form a CP-Cas9 variant. [00140] Exemplary CP-Cas9 amino acid sequences, based on the Cas9 of SEQ ID NO: 6, are provided below in which linker sequences are indicated by underlining and optional methionine (M) residues are indicated in bold. It should be appreciated that the disclosure provides CP-Cas9 sequences that do not include a linker sequence or that include different linker sequences. It should be appreciated that CP-Cas9 sequences may be based on Cas9 sequences other than that of SEQ ID NO: 6 and any examples provided herein are not meant to be limiting.

[00141] CP1012

[00146] Exemplary C-terminal fragments of Cas9, based on the Cas9 of SEQ ID NO: 6, which may be rearranged to an N-terminus of Cas9, are provided below. It should be appreciated that such C- terminal fragments of Cas9 are exemplary and are not meant to be limiting.

Cas9 domains

[00152] Some aspects of this disclosure provide Cas9 proteins that exhibit activity on a target sequence that does not comprise the canonical PAM (5¢-NGG-3¢, where N is A, C, G, or T) at its 3¢- end. In some embodiments, the Cas9 protein exhibits activity on a target sequence comprising a 5¢- NGG-3¢ PAM sequence at its 3¢-end. In some embodiments, the Cas9 protein exhibits activity on a target sequence comprising a 5´-NNG-3´ PAM sequence at its 3¢-end. In some embodiments, the Cas9 protein exhibits activity on a target sequence comprising a 5¢-NNA-3¢ PAM sequence at its 3ʹ-end. In some embodiments, the Cas9 protein exhibits activity on a target sequence comprising a 5¢-NNC-3¢ PAM sequence at its 3ʹ-end. In some embodiments, the Cas9 protein exhibits activity on a target sequence comprising a 5´-NNT-3´ PAM sequence at its 3ʹ-end. In some embodiments, the Cas9 protein exhibits activity on a target sequence comprising a 5´-NGT-3´ PAM sequence at its 3ʹ-end. In some embodiments, the Cas9 protein exhibits activity on a target sequence comprising a 5´-NGA-3´ PAM sequence at its 3ʹ-end. In some embodiments, the Cas9 protein exhibits activity on a target sequence comprising a 5´-NGC-3´ PAM sequence at its 3ʹ-end. In some embodiments, the Cas9 protein exhibits activity on a target sequence comprising a 5´-NAA-3´ PAM sequence at its 3´-end. In some embodiments, the Cas9 protein exhibits activity on a target sequence comprising a 5´-NAC-3´ PAM sequence at its 3¢-end. In some embodiments, the Cas9 protein exhibits activity on a target sequence comprising a 5´-NAT-3´ PAM sequence at its 3´-end. In still other embodiments, the Cas9 protein exhibits activity on a target sequence comprising a 5´-NAG-3´ PAM sequence at its 3´-end.

[00153] It should be appreciated that any of the amino acid mutations described herein, (e.g., A262T) from a first amino acid residue (e.g., A) to a second amino acid residue (e.g., T) may also include mutations from the first amino acid residue to an amino acid residue that is similar to (e.g., conserved) the second amino acid residue. For example, mutation of an amino acid with a hydrophobic side chain (e.g., alanine, valine, isoleucine, leucine, methionine, phenylalanine, tyrosine, or tryptophan) may be a mutation to a second amino acid with a different hydrophobic side chain (e.g., alanine, valine, isoleucine, leucine, methionine, phenylalanine, tyrosine, or tryptophan). For example, a mutation of an alanine to a threonine (e.g., a A262T mutation) may also be a mutation from an alanine to an amino acid that is similar in size and chemical properties to a threonine, for example, serine. As another example, mutation of an amino acid with a positively charged side chain (e.g., arginine, histidine, or lysine) may be a mutation to a second amino acid with a different positively charged side chain (e.g., arginine, histidine, or lysine). As another example, mutation of an amino acid with a polar side chain (e.g., serine, threonine, asparagine, or glutamine) may be a mutation to a second amino acid with a different polar side chain (e.g., serine, threonine, asparagine, or glutamine). Additional similar amino acid pairs include, but are not limited to, the following: phenylalanine and tyrosine; asparagine and glutamine; methionine and cysteine; aspartic acid and glutamic acid; and arginine and lysine. The skilled artisan would recognize that such conservative amino acid substitutions will likely have minor effects on protein structure and are likely to be well tolerated without compromising function. In some embodiments, any amino of the amino acid mutations provided herein from one amino acid to a threonine may be an amino acid mutation to a serine. In some embodiments, any amino of the amino acid mutations provided herein from one amino acid to an arginine may be an amino acid mutation to a lysine. In some embodiments, any amino of the amino acid mutations provided herein from one amino acid to an isoleucine, may be an amino acid mutation to an alanine, valine, methionine, or leucine. In some embodiments, any amino of the amino acid mutations provided herein from one amino acid to a lysine may be an amino acid mutation to an arginine. In some embodiments, any amino of the amino acid mutations provided herein from one amino acid to an aspartic acid may be an amino acid mutation to a glutamic acid or asparagine. In some embodiments, any amino of the amino acid mutations provided herein from one amino acid to a valine may be an amino acid mutation to an alanine, isoleucine, methionine, or leucine. In some embodiments, any amino of the amino acid mutations provided herein from one amino acid to a glycine may be an amino acid mutation to an alanine. It should be appreciated, however, that additional conserved amino acid residues would be recognized by the skilled artisan and any of the amino acid mutations to other conserved amino acid residues are also within the scope of this disclosure.

Mutations in Wild-Type SpCas9

[00154] Some aspects of this disclosure provide a Cas9 protein comprising an amino acid sequence that is at least 80% identical to the amino acid sequence of Cas9 as provided by any of the sequences set forth in SEQ ID NO: 2, 4, or 6-11, wherein the amino acid sequence of the Cas9 protein comprises at least one mutation in an amino acid residue selected from the group consisting of amino acid residues 10, 177, 218, 322, 367, 409, 427, 589, 599, 614, 630, 631, 654, 673, 693, 710, 715, 727, 743, 753, 757, 758, 762, 763, 768, 803, 859, 861, 865, 869, 921, 946, 1016, 1021, 1028, 1054, 1077, 1080, 1114, 1134, 1135, 1137, 1139, 1151, 1180, 1188, 1211, 1219, 1221, 1223, 1256, 1264, 1274, 1290, 1318, 1317, 1320, 1323, and 1333 of S. pyogenes having the amino acid sequence provided in SEQ ID NO: 2, or in a corresponding amino acid residue in any of the amino acid sequences provided in SEQ ID NO: 2. In some embodiments, the Cas9 protein comprises a RuvC and an HNH domain. In some embodiments, the amino acid sequence of the Cas9 protein is not identical to the amino acid sequence of a naturally occurring Cas9 domain. In some embodiments, the Cas9 protein is a nuclease- inactive Cas9 protein. In some embodiments, the Cas9 domain is a Cas9 nickase. In some embodiments, the amino acid sequence of the Cas9 protein comprises at least one mutation selected from the group consisting of X10T, X177N, X218R, X322V, X367T, X409I, X427G, X589S, X599R, X614N, X630K, X631A, X654L, X673E, X693L, X710E, X715C, X727I, X743I, X753G, X757K, X758H, X762G, X763I, X768H, X803S, X859S, X861N, X865G, X869S, X921P, X946D, X1016D, X1021T, X1028D, X1054D, X1077D, X1080S, X1114G, X1134L, X1135N, X1137S, X1139A, X1151E, X1180G, X1188R, X1211R, X1219V, X1221H, X1223S, X1256R, X1264Y, X1274R, X1290G, X1318S, X1317T, X1320V, X1323D, and X1333K of the amino acid sequence provided in SEQ ID NO: 2, or in a corresponding mutation, or mutations, in any of the amino acid sequences provided in SEQ ID NO: 2, wherein X represents any amino acid. In some embodiments, the amino acid sequence of the Cas9 protein comprises at least one mutation selected from group consisting of A10T, D177N, K218R, I322V, A367T, S409I, E427G, A589S, K599R, D614N, E630K, M631A, R654L, K673E, F693L, K710E, G715C, L727I, V743I, R753G, E757K, N758H, E762G, M763I, Q768H, N803S, R859S, D861N, G865G, N869S, L921P, N946D, Y1016D, M1021T, E1028D, V1139A, N1054D, G1077D, F1080S, R1114G, F1134L, D1135N, P1137S, K1151E, D1180G, K1188R, K1211R, E1219V, Q1221H, G1223S, Q1256R, H1264Y, S1274R, V1290G, L1318S, N1317T, A1320V, A1323D, and R1333K of the amino acid sequence provided in SEQ ID NO: 2, or in a corresponding mutation, or mutations, in any of the amino acid sequences provided in SEQ ID NO: 2, 4, or 6-11, wherein X represents any amino acid.

[00155] Some aspects of this disclosure provide a Cas9 protein comprising an amino acid sequence that is at least 80% identical to the amino acid sequence of Cas9 as provided by SEQ ID NO: 2, wherein the amino acid sequence of the Cas9 protein comprises at least one mutation in an amino acid residue selected from the group consisting of amino acid residues 472, 562, 565, 570, 589, 608, 625, 627, 629, 630, 631, 638, 647, 652, 653, 654, 670, 673, 676, 687, 703, 710, 711, 716, 740, 742, 752, 753, 767, 771, 775, 789, 790, 795, 797, 803, 804, 808, 848, 866, 875, 890, 922, 928, 948, 959, 990, 995, 1014, 1015, 1016, 1021, 1030, 1036, 1055, 1057, 1114, 1127, 1135, 1156, 1177, 1180, 1184, 1207, 1219, 1234, 1246, 1251, 1252, 1286, 1301, 1332, 1335, 1337, 1338, 1348, 1349, 1365, 1367, and 1368 of S. pyogenes having the amino acid sequence provided in SEQ ID NO: 2, or in a corresponding amino acid residue in any of the amino acid sequences provided in SEQ ID NO: 2, 4, or 6-11. In some embodiments, the Cas9 protein comprises a RuvC and an HNH domain.

[00156] In some embodiments, the amino acid sequence of the Cas9 protein is not identical to the amino acid sequence of a naturally occurring Cas9 protein. In some embodiments, the Cas9 protein is a nuclease-inactive Cas9 protein. In some embodiments, the Cas9 protein is a Cas9 nickase. In some embodiments, the amino acid sequence of the Cas9 protein comprises at least one mutation selected from the group consisting of X472I, X562F, X565D, X570T, X570S, X589V, X608R, X625S, X627K, X629G, X630G, X631I, X638P, X647A, X647I, X652T, X653K, X654L, X654I, X654H, X670T, X673E, X676G, X687R, X703P, X710E, X711T, X716R, X740A, X742E, X752R, X753G, X767D, X771H, X775R, X789E, X790A, X795L, X797N, X803S, X804A, X808D, X848N, X866R, X875I, X890E, X890N, X922A, X928T, X948E, X959N, X990S, X995S, X1014N, X1015A, X1016C, X1016S, X1021L, X1030R, X1036H, X1036D, X1055E, X1057S, X1057T, X1114G, X1127A, X1135N, X1156E, X1156N, X1177S, X1180E, X1184T, X1207G, X1219V, X1234D, X1246E, X1251G, X1252D, X1286H, X1301S, X1332N, X1332G, X1335Q, X1337N, X1338T, X1348V, X1349R, X1365L, X1367E, X1367T, X1367fs?, and X1368D of the amino acid sequence provided in SEQ ID NO: 2, or in a corresponding mutation, or mutations, in any of the amino acid sequences provided in SEQ ID NOs: 2, 4, or 6-11, wherein X represents any amino acid. In some embodiments, the amino acid sequence of the Cas9 protein comprises at least one mutation selected from group consisting of T472I, I562F, V565D, I570T, I570S, A589V, K608R, L625S, E627K, R629G, E630G, M631I, T638P, V647A, V647I, K652T, R653K, R654L, R654I, R654H, I670T, K673E, G676G, G687R, T703P, K710E, A711T, Q716R, T740A, K742E, G752R, R753G, N767D, Q771H, K775R, K789E, E790A, I795L, K797N, N803S, T804A, N808D, K848N, K866R, V875I, K890E, K890N, V922A, K948E, K959N, N990S, T995S, K1014N, V1015A, Y1016C, Y1016S, M1021L, G1030R, Y1036H, Y1036D, I1055E, I1057S, I1057T, R1114G, D1127A, D1135N, K1156E, K1156N, N1177S, D1180E, A1184T, E1207G, E1219V, N1234D, K1246E, D1251G, N1252D, N1286H, P1301S, D1332N, D1332G, R1335Q, T1337N, S1338T, I1348V, H1349R, L1365L, G1367E, G1367T, and D1368D of the amino acid sequence provided in SEQ ID NO: 2, or in a corresponding mutation, or mutations, in SEQ ID NO: 2, 4, or 6-11, wherein X represents any amino acid. [00157] Some aspects of this disclosure provide a Cas9 protein comprising an amino acid sequence that is at least 80% identical to the amino acid sequence of Cas9 as provided by SEQ ID NOs: 2, wherein the amino acid sequence of the Cas9 protein comprises at least one mutation in an amino acid residue selected from the group consisting of amino acid residues 575, 596, 631, 649, 654, 664, 710, 740, 743, 748, 750, 753, 765, 790, 797, 853, 922, 955, 961, 985, 1012, 1049, 1057, 1114, 1131, 1135, 1150, 1156, 1162, 1180, 1191, 1218, 1219, 1221, 1227, 1249, 1253, 1256, 1286, 1293, 1308, 1317, 1320, 1321, 1332, 1335, and 1339 of S. pyogenes having the amino acid sequence provided in SEQ ID NO: 2, or in a corresponding amino acid residue in another Cas9 sequence (e.g., any of the sequences of 2, 4, or 6-11). In some embodiments, the Cas9 protein comprises a RuvC and an HNH domain. In some embodiments, the amino acid sequence of the Cas9 protein is not identical to the amino acid sequence of a naturally occurring Cas9 protein. In some embodiments, the Cas9 protein is a nuclease-inactive Cas9 domain. In some embodiments, the Cas9 protein is a Cas9 nickase. In some embodiments, the amino acid sequence of the Cas9 protein comprises at least one mutation selected from the group consisting of X575S, X596Y, X631L, X649R, X654L, X664K, X710E, X740A, X743I, X748I, X750A, X753G, X765X, X790A, X797E, X853E, X922A, X955L, X961E, X985Y, X1012A, X1049G, X1057V, X1114G, X1131C, X1135N, X1150V, X1156E, X1162A, X1180G, X1180A, X1191N, X1218S, X1219V, X1221H, X1227V, X1249S, X1253K, X1256R, X1286K, X1293T, X1308D, X1317K, X1320V, X1321S, X1332G, X1335L, and X1339I of the amino acid sequence provided in SEQ ID NO: 2, or in a corresponding mutation, or mutations, in another Cas9 sequence (e.g., any of the sequences of SEQ ID NOs: 2, 4, or 6-11), wherein X represents any amino acid. In some embodiments, the amino acid sequence of the Cas9 protein comprises at least one mutation selected from group consisting of F575S, D596Y, M631L, K649R, R654L, R664K, K710E, T740A, V743I, V748I, V750A, R753G, R765X, E790A, K797E, D853E, V922A, V955L, K961E, H985Y, D1012A, E1049G, I1057V, R1114G, Y1131C, D1135N, E1150V, K1156E, E1162A, D1180G, D1180A, K1191N, G1218S, E1219V, Q1221H, A1227V, P1249S, E1253K, Q1256R, N1286K, A1293T, N1308D, N1317K, A1320V, P1321S, D1332G, R1335L, and T1339I of the amino acid sequence provided in SEQ ID NO: 2, or in a corresponding mutation, or mutations, in another Cas9 sequence (e.g., any of the sequences of SEQ ID NOs: 2, 4, or 6-11), wherein X represents any amino acid.

[00158] In some embodiments, the amino acid sequence of the Cas9 protein comprises at least one, at least two, at least three, at least four, at least five, at least six, at least seven, at least eight, at least nine, at least ten, at least eleven, at least twelve, at least thirteen, at least fourteen, at least fifteen, at least sixteen, at least seventeen, at least eighteen, at least nineteen, at least twenty, at least twenty-one, at least twenty-two, at least twenty-three, at least twenty-four, at least twenty-five, at least twenty-six, at least twenty-seven, at least twenty-eight, at least twenty-nine, at least thirty, at least thirty-one, at least thirty-two, at least thirty-three, at least thirty-four, at least thirty-five, at least thirty-six, at least thirty-seven, at least thirty-eight, at least thirty-nine, at least forty, at least forty-one, at least forty-two, at least forty-three, at least forty-four, at least forty-five, at least forty-six, at least forty-seven, at least forty-eight, at least forty-nine, at least fifty, at least fifty-one, at least fifty-two, at least fifty-three, at least fifty-four, at least fifty-five, at least fifty-six, at least fifty-seven, at least fifty-eight, or at least fifty-nine mutations in amino acid residues selected from the group consisting of 10, 177, 218, 322, 367, 409, 427, 589, 599, 614, 630, 631, 654, 673, 693, 710, 715, 727, 743, 753, 757, 758, 762, 763, 768, 803, 859, 861, 865, 869, 921, 946, 1016, 1021, 1028, 1054, 1077, 1080, 1114, 1134, 1135, 1137, 1139, 1151, 1180, 1188, 1211, 1219, 1221, 1223, 1256, 1264, 1274, 1290, 1318, 1317, 1320, 1323, and 1333 of the amino acid sequence provided in SEQ ID NO: 2, or in a corresponding mutation, or mutations, in another Cas9 sequence (e.g., any of the sequences of SEQ ID NOs: 2, 4, or 6-11), wherein X represents any amino acid.

[00159] In some embodiments, the amino acid sequence of the Cas9 protein comprises at least one, at least two, at least three, at least four, at least five, at least six, at least seven, at least eight, at least nine, at least ten, at least eleven, at least twelve, at least thirteen, at least fourteen, at least fifteen, at least sixteen, at least seventeen, at least eighteen, at least nineteen, at least twenty, at least twenty-one, at least twenty-two, at least twenty-three, at least twenty-four, at least twenty-five, at least twenty-six, at least twenty-seven, at least twenty-eight, at least twenty-nine, at least thirty, at least thirty-one, at least thirty-two, at least thirty-three, at least thirty-four, at least thirty-five, at least thirty-six, at least thirty-seven, at least thirty-eight, at least thirty-nine, at least forty, at least forty-one, at least forty-two, at least forty-three, at least forty-four, at least forty-five, at least forty-six, at least forty-seven, at least forty-eight, at least forty-nine, at least fifty, at least fifty-one, at least fifty-two, at least fifty-three, at least fifty-four, at least fifty-five, at least fifty-six, at least fifty-seven, at least fifty-eight, or at least fifty-nine mutations selected from the group consisting of X10T, X177N, X218R, X322V, X367T, X409I, X427G, X589S, X599R, X614N, X630K, X631A, X654L, X673E, X693L, X710E, X715C, X727I, X743I, X753G, X757K, X758H, X762G, X763I, X768H, X803S, X859S, X861N, X865G, X869S, X921P, X946D, X1016D, X1021T, X1028D, X1054D, X1077D, X1080S, X1114G, X1134L, X1135N, X1137S, X1139A, X1151E, X1180G, X1188R, X1211R, X1219V, X1221H, X1223S, X1256R, X1264Y, X1274R, X1290G, X1318S, X1317T, X1320V, X1323D, and X1333K of the amino acid sequence provided in SEQ ID NO: 2, or in a corresponding mutation, or mutations, in another Cas9 sequence (e.g., any of the sequences of SEQ ID NOs: 2, 4, or 6-11), wherein X represents any amino acid.

[00160] In some embodiments, the present disclosure may utilize any of the Cas9 variants disclosed in the SEQUENCES section herein.

[00161] In some embodiments, the amino acid sequence of the Cas9 protein comprises at least one, at least two, at least three, at least four, at least five, at least six, at least seven, at least eight, at least nine, at least ten, at least eleven, at least twelve, at least thirteen, at least fourteen, at least fifteen, at least sixteen, at least seventeen, at least eighteen, at least nineteen, at least twenty, at least twenty-one, at least twenty-two, at least twenty-three, at least twenty-four, at least twenty-five, at least twenty-six, at least twenty-seven, at least twenty-eight, at least twenty-nine, at least thirty, at least thirty-one, at least thirty-two, at least thirty-three, at least thirty-four, at least thirty-five, at least thirty-six, at least thirty-seven, at least thirty-eight, at least thirty-nine, at least forty, at least forty-one, at least forty-two, at least forty-three, at least forty-four, at least forty-five, at least forty-six, at least forty-seven, at least forty-eight, at least forty-nine, at least fifty, at least fifty-one, at least fifty-two, at least fifty-three, at least fifty-four, at least fifty-five, at least fifty-six, at least fifty-seven, at least fifty-eight, or at least fifty-nine mutations selected from the group consisting of A10T, D177N, K218R, I322V, A367T, S409I, E427G, A589S, K599R, D614N, E630K, M631A, R654L, K673E, F693L, K710E, G715C, L727I, V743I, R753G, E757K, N758H, E762G, M763I, Q768H, N803S, R859S, D861N, G865G, N869S, L921P, N946D, Y1016D, M1021T, E1028D, N1054D, G1077D, F1080S, R1114G, F1134L, D1135N, P1137S, V1139A, K1151E, D1180G, K1188R, K1211R, E1219V, Q1221H, G1223S, Q1256R, H1264Y, S1274R, V1290G, L1318S, N1317T, A1320V, A1323D, and R1333K of the amino acid sequence provided in SEQ ID NO: 2, or in a corresponding mutation, or mutations, in another Cas9 sequence (e.g., any of the sequences of SEQ ID NOs: 2, 4, or 6-11), wherein X represents any amino acid.

[00162] In some embodiments, the amino acid sequence of the Cas9 protein comprises at least one, at least two, at least three, at least four, at least five, at least six, at least seven, at least eight, at least nine, at least ten, at least eleven, at least twelve, at least thirteen, at least fourteen, at least fifteen, at least sixteen, at least seventeen, at least eighteen, at least nineteen, at least twenty, at least twenty-one, at least twenty-two, at least twenty-three, at least twenty-four, at least twenty-five, at least twenty-six, at least twenty-seven, at least twenty-eight, at least twenty-nine, at least thirty, at least thirty-one, at least thirty-two, at least thirty-three, at least thirty-four, at least thirty-five, at least thirty-six, at least thirty-seven, at least thirty-eight, at least thirty-nine, at least forty, at least forty-one, at least forty-two, at least forty-three, at least forty-four, at least forty-five, at least forty-six, at least forty-seven, or at least forty-eight mutations selected from the group consisting of 10, 177, 218, 322, 367, 427, 589, 599, 614, 630, 631, 693, 710, 743, 753, 757, 758, 762, 768, 803, 859, 861, 865, 869, 921, 946, 1016, 1021, 1028, 1054, 1077, 1080, 1114, 1134, 1135, 1137, 1151, 1180, 1188, 1211, 1221, 1223, 1274, 1290, 1317, 1320, 1323, and 1333 of the amino acid sequence provided in SEQ ID NO: 2, or in a corresponding mutation, or mutations, in another Cas9 sequence (e.g., any of the sequences of SEQ ID NOs: 2, 4, or 6-11), wherein X represents any amino acid.

[00163] In some embodiments, the amino acid sequence of the Cas9 protein comprises at least one, at least two, at least three, at least four, at least five, at least six, at least seven, at least eight, at least nine, at least ten, at least eleven, at least twelve, at least thirteen, at least fourteen, at least fifteen, at least sixteen, at least seventeen, at least eighteen, at least nineteen, at least twenty, at least twenty-one, at least twenty-two, at least twenty-three, at least twenty-four, at least twenty-five, at least twenty-six, at least twenty-seven, at least twenty-eight, at least twenty-nine, at least thirty, at least thirty-one, at least thirty-two, at least thirty-three, at least thirty-four, at least thirty-five, at least thirty-six, at least thirty-seven, at least thirty-eight, at least thirty-nine, at least forty, at least forty-one, at least forty-two, at least forty-three, at least forty-four, at least forty-five, at least forty-six, at least forty-seven, or at least forty-eight mutations selected from the group consisting of X10T, X177N, X218R, X322V, X367T, X427G, X589S, X599R, X614N, X630K, X631A, X693L, X710E, X743I, X753G, X757K, X758H, X762G, X768H, X803S, X859S, X861N, X865G, X869S, X921P, X946D, X1016D, X1021T, X1028D, X1054D, X1077D, X1080S, X1114G, X1134L, X1135N, X1137S, X1151E, X1180G, X1188R, X1211R, X1221H, X1223S, X1274R, X1290G, X1317T, X1320V, X1323D, and X1333K of the amino acid sequence provided in SEQ ID NO: 2, or in a corresponding mutation, or mutations, in another Cas9 sequence (e.g., any of the sequences of SEQ ID NOs: 2, 4, or 6-11), wherein X represents any amino acid.

[00164] In some embodiments, the amino acid sequence of the Cas9 protein comprises at least one, at least two, at least three, at least four, at least five, at least six, at least seven, at least eight, at least nine, at least ten, at least eleven, at least twelve, at least thirteen, at least fourteen, at least fifteen, at least sixteen, at least seventeen, at least eighteen, at least nineteen, at least twenty, at least twenty-one, at least twenty-two, at least twenty-three, at least twenty-four, at least twenty-five, at least twenty-six, at least twenty-seven, at least twenty-eight, at least twenty-nine, at least thirty, at least thirty-one, at least thirty-two, at least thirty-three, at least thirty-four, at least thirty-five, at least thirty-six, at least thirty-seven, at least thirty-eight, at least thirty-nine, at least forty, at least forty-one, at least forty-two, at least forty-three, at least forty-four, at least forty-five, at least forty-six, at least forty-seven, or at least forty-eight mutations selected from the group consisting of A10T, D177N, K218R, I322V, A367T, E427G, A589S, K599R, D614N, E630K, M631A, F693L, K710E, V743I, R753G, E757K, N758H, E762G, Q768H, N803S, R859S, D861N, N869S, L921P, N946D, Y1016D, M1021T, Q1028D, N1054D, G1077D, F1080S, R1114G, F1134L, D1135N, P1137S, K1151E, D1180G, K1188R, K1211R, Q1221H, G1223S, S1274R, V1290G, N1317T, A1320V, A1323D, and R1333K of the amino acid sequence provided in SEQ ID NO: 2, or in a corresponding mutation, or mutations, in another Cas9 sequence (e.g., any of the sequences of SEQ ID NOs: 2, 4, or 6-11), wherein X represents any amino acid.

[00165] In some embodiments, the amino acid sequence of the Cas9 protein comprises at least one, at least two, at least three, at least four, at least five, at least six, at least seven, at least eight, at least nine, at least ten, at least eleven, at least twelve, at least thirteen, at least fourteen, at least fifteen, at least sixteen, at least seventeen, at least eighteen, at least nineteen, at least twenty, at least twenty-one, at least twenty-two, at least twenty-three, at least twenty-four, at least twenty-five, at least twenty-six, at least twenty-seven, at least twenty-eight, at least twenty-nine, at least thirty, at least thirty-one, at least thirty-two, at least thirty-three, at least thirty-four, at least thirty-five, at least thirty-six, at least thirty-seven, at least thirty-eight, at least thirty-nine, at least forty, at least forty-one, at least forty-two, at least forty-three, at least forty-four, at least forty-five, at least forty-six, at least forty-seven, at least forty-eight, at least forty-nine, at least fifty, at least fifty-one, at least fifty-two, at least fifty-three, at least fifty-four, at least fifty-five, at least fifty-six, at least fifty-seven, at least fifty-eight, at least fifty- nine, at least sixty, at least sixty-one, at least sixty-two, at least sixty-three, at least sixty-four, at least sixty-five, at least sixty-six, at least sixty-seven, at least sixty-eight, at least sixty-nine, at least seventy, at least seventy-one, at least seventy-two, at least seventy-three, at least seventy-four, at least seventy-five, at least seventy-six, at least seventy-seven, at least seventy-eight, at least seventy-nine, or at least eighty mutations selected from the group consisting of 472, 562, 565, 570, 589, 608, 625, 627, 629, 630, 631, 638, 647, 647, 652, 653, 654, 670, 673, 676, 687, 703, 710, 711, 716, 740, 742, 752, 753, 767, 771, 775, 789, 790, 795, 797, 803, 804, 808, 848, 866, 875, 890, 922, 928, 948, 959, 990, 995, 1014, 1015, 1016, 1021, 1030, 1036, 1055, 1057, 1114, 1127, 1135, 1156, 1177, 1180, 1184, 1207, 1219, 1234, 1246, 1251, 1252, 1286, 1301, 1332, 1335, 1337, 1338, 1348, 1349, 1365, 1367, and 1368 of the amino acid sequence provided in SEQ ID NO: 2, or in a corresponding mutation, or mutations, in another Cas9 sequence (e.g., any of the sequences of SEQ ID NOs: 2, 4, or 6-11), wherein X represents any amino acid.

[00166] In some embodiments, the amino acid sequence of the Cas9 protein comprises at least one, at least two, at least three, at least four, at least five, at least six, at least seven, at least eight, at least nine, at least ten, at least eleven, at least twelve, at least thirteen, at least fourteen, at least fifteen, at least sixteen, at least seventeen, at least eighteen, at least nineteen, at least twenty, at least twenty-one, at least twenty-two, at least twenty-three, at least twenty-four, at least twenty-five, at least twenty-six, at least twenty-seven, at least twenty-eight, at least twenty-nine, at least thirty, at least thirty-one, at least thirty-two, at least thirty-three, at least thirty-four, at least thirty-five, at least thirty-six, at least thirty-seven, at least thirty-eight, at least thirty-nine, at least forty, at least forty-one, at least forty-two, at least forty-three, at least forty-four, at least forty-five, at least forty-six, at least forty-seven, at least forty-eight, at least forty-nine, at least fifty, at least fifty-one, at least fifty-two, at least fifty-three, at least fifty-four, at least fifty-five, at least fifty-six, at least fifty-seven, at least fifty-eight, at least fifty- nine, at least sixty, at least sixty-one, at least sixty-two, at least sixty-three, at least sixty-four, at least sixty-five, at least sixty-six, at least sixty-seven, at least sixty-eight, at least sixty-nine, at least seventy, at least seventy-one, at least seventy-two, at least seventy-three, at least seventy-four, at least seventy-five, at least seventy-six, at least seventy-seven, at least seventy-eight, at least seventy-nine, or at least eighty mutations selected from the group consisting of X472I, X562F, X565D, X570T, X570S, X589V, X608R, X625S, X627K, X629G, X630G, X631I, X638P, X647A, X647I, X652T, X653K, X654L, X654I, X654H, X670T, X673E, X676G, X687R, X703P, X710E, X711T, X716R, X740A, X742E, X752R, X753G, X767D, X771H, X775R, X789E, X790A, X795L, X797N, X803S, X804A, X808D, X848N, X866R, X875I, X890E, X890N, X922A, X928T, X948E, X959N, X990S, X995S, X1014N, X1015A, X1016C, X1016S, X1021L, X1030R, X1036H, X1036D, X1055E, X1057S, X1057T, X1114G, X1127A, X1135N, X1156E, X1156N, X1177S, X1180E, X1184T, X1207G, X1219V, X1234D, X1246E, X1251G, X1252D, X1286H, X1301S, X1332N, X1332G, X1335Q, X1337N, X1338T, X1348V, X1349R, X1365L, X1367E, X1367T, X1367fs?, and X1368D of the amino acid sequence provided in SEQ ID NO: 2, or in a corresponding mutation, or mutations, in another Cas9 sequence (e.g., any of the sequences of SEQ ID NOs: 2, 4, or 6-11), wherein X represents any amino acid.

[00167] In some embodiments, the amino acid sequence of the Cas9 protein comprises at least one, at least two, at least three, at least four, at least five, at least six, at least seven, at least eight, at least nine, at least ten, at least eleven, at least twelve, at least thirteen, at least fourteen, at least fifteen, at least sixteen, at least seventeen, at least eighteen, at least nineteen, at least twenty, at least twenty-one, at least twenty-two, at least twenty-three, at least twenty-four, at least twenty-five, at least twenty-six, at least twenty-seven, at least twenty-eight, at least twenty-nine, at least thirty, at least thirty-one, at least thirty-two, at least thirty-three, at least thirty-four, at least thirty-five, at least thirty-six, at least thirty-seven, at least thirty-eight, at least thirty-nine, at least forty, at least forty-one, at least forty-two, at least forty-three, at least forty-four, at least forty-five, at least forty-six, at least forty-seven, at least forty-eight, at least forty-nine, at least fifty, at least fifty-one, at least fifty-two, at least fifty-three, at least fifty-four, at least fifty-five, at least fifty-six, at least fifty-seven, at least fifty-eight, at least fifty- nine, at least sixty, at least sixty-one, at least sixty-two, at least sixty-three, at least sixty-four, at least sixty-five, at least sixty-six, at least sixty-seven, at least sixty-eight, at least sixty-nine, at least seventy, at least seventy-one, at least seventy-two, at least seventy-three, at least seventy-four, at least seventy-five, at least seventy-six, at least seventy-seven, at least seventy-eight, at least seventy-nine, at least eighty mutations selected from the group consisting of T472I, I562F, V565D, I570T, I570S, A589V, K608R, L625S, E627K, R629G, E630G, M631I, T638P, V647A, V647I, K652T, R653K, R654L, R654I, R654H, I670T, K673E, G676G, G687R, T703P, K710E, A711T, Q716R, T740A, K742E, G752R, R753G, N767D, Q771H, K775R, K789E, E790A, I795L, K797N, N803S, T804A, N808D, K848N, K866R, V875I, K890E, K890N, V922A, K948E, K959N, N990S, T995S, K1014N, V1015A, Y1016C, Y1016S, M1021L, G1030R, Y1036H, Y1036D, I1055E, I1057S, I1057T, R1114G, D1127A, D1135N, K1156E, K1156N, N1177S, D1180E, A1184T, E1207G, E1219V, N1234D, K1246E, D1251G, N1252D, N1286H, P1301S, D1332N, D1332G, R1335Q, T1337N, S1338T, I1348V, H1349R, L1365L, G1367E, G1367T, and D1368D of the amino acid sequence provided in SEQ ID NO: 2, or in a corresponding mutation, or mutations, in another Cas9 sequence (e.g., any of the sequences of SEQ ID NOs: 2, 4, or 6-11), wherein X represents any amino acid.

[00168] In some embodiments, the amino acid sequence of the Cas9 protein comprises at least one, at least two, at least three, at least four, at least five, at least six, at least seven, at least eight, at least nine, at least ten, at least eleven, at least twelve, at least thirteen, at least fourteen, at least fifteen, at least sixteen, at least seventeen, at least eighteen, at least nineteen, at least twenty, at least twenty-one, at least twenty-two, at least twenty-three, at least twenty-four, at least twenty-five, at least twenty-six, at least twenty-seven, at least twenty-eight, at least twenty-nine, at least thirty, at least thirty-one, at least thirty-two, at least thirty-three, at least thirty-four, at least thirty-five, at least thirty-six, at least thirty-seven, at least thirty-eight, at least thirty-nine, at least forty, at least forty-one, at least forty-two, at least forty-three, at least forty-four, at least forty-five, at least forty-six, at least forty-seven, at least forty-eight, at least forty-nine, at least fifty, at least fifty-one, at least fifty-two, at least fifty-three, at least fifty-four, at least fifty-five, at least fifty-six, at least fifty-seven, at least fifty-eight, at least fifty- nine, at least sixty, at least sixty-one, at least sixty-two, at least sixty-three, at least sixty-four, at least sixty-five, at least sixty-six, at least sixty-seven, at least sixty-eight, at least sixty-nine, at least seventy, at least seventy-one, or at least seventy-two mutations in amino acid residues selected from the group consisting of 472, 562, 565, 570, 589, 608, 625, 627, 629, 630, 631, 638, 647, 647, 652, 653, 654, 676, 687, 703, 716, 740, 742, 752, 753, 767, 771, 775, 789, 790, 795, 797, 803, 804, 808, 848, 866, 875, 890, 890, 922, 948, 959, 990, 995, 1014, 1015, 1016, 1021, 1030, 1036, 1055, 1057, 1057, 1114, 1127, 1135, 1156, 1177, 1180, 1184, 1234, 1246, 1251, 1252, 1286, 1301, 1332, 1335, 1348, 1367, and 1368 of the amino acid sequence provided in SEQ ID NO: 2, or in a corresponding mutation, or mutations, in another Cas9 sequence (e.g., any of the sequences of SEQ ID NOs: 2, 4, or 6-11), wherein X represents any amino acid.

[00169] In some embodiments, the amino acid sequence of the Cas9 protein comprises at least one, at least two, at least three, at least four, at least five, at least six, at least seven, at least eight, at least nine, at least ten, at least eleven, at least twelve, at least thirteen, at least fourteen, at least fifteen, at least sixteen, at least seventeen, at least eighteen, at least nineteen, at least twenty, at least twenty-one, at least twenty-two, at least twenty-three, at least twenty-four, at least twenty-five, at least twenty-six, at least twenty-seven, at least twenty-eight, at least twenty-nine, at least thirty, at least thirty-one, at least thirty-two, at least thirty-three, at least thirty-four, at least thirty-five, at least thirty-six, at least thirty-seven, at least thirty-eight, at least thirty-nine, at least forty, at least forty-one, at least forty-two, at least forty-three, at least forty-four, at least forty-five, at least forty-six, at least forty-seven, at least forty-eight, at least forty-nine, at least fifty, at least fifty-one, at least fifty-two, at least fifty-three, at least fifty-four, at least fifty-five, at least fifty-six, at least fifty-seven, at least fifty-eight, at least fifty- nine, at least sixty, at least sixty-one, at least sixty-two, at least sixty-three, at least sixty-four, at least sixty-five, at least sixty-six, at least sixty-seven, at least sixty-eight, at least sixty-nine, at least seventy, at least seventy-one, or at least seventy-two mutations selected from the group consisting of X472I, X562F, X565D, X570T, X570S, X589V, X608R, X625S, X627K, X629G, X630G, X631I, X631V, X638P, X647A, X647I, X652T, X653K, X654L, X654I, X654H, X670T, X676G, X687R, X703P, X710E, X716R, X740A, X742E, X752R, X753G, X767D, X771H, X775R, X789E, X790A, X795L, X797N, X803S, X804A, X808D, X848N, X866R, X875I, X890E, X890N, X922A, X948E, X959N, X990S, X995S, X1014N, X1015A, X1016C, X1016S, X1021L, X1030R, X1036H, X1036D, X1055E, X1057S, X1057T, X1114G, X1127A, X1127G, X1135N, X1156E, X1156N, X1177S, X1180E, X1184T, X1234D, X1246E, X1251G, X1252D, X1286H, X1301S, X1332N, X1332G, X1335Q, X1338T, X1348V, X1349R, X1367E, X1367T, X1367fs?, and X1368D of the amino acid sequence provided in SEQ ID NO: 2, or in a corresponding mutation, or mutations, in another Cas9 sequence (e.g., any of the sequences of SEQ ID NOs: 2, 4, or 6-11), wherein X represents any amino acid.

[00170] In some embodiments, the amino acid sequence of the Cas9 protein comprises at least one, at least two, at least three, at least four, at least five, at least six, at least seven, at least eight, at least nine, at least ten, at least eleven, at least twelve, at least thirteen, at least fourteen, at least fifteen, at least sixteen, at least seventeen, at least eighteen, at least nineteen, at least twenty, at least twenty-one, at least twenty-two, at least twenty-three, at least twenty-four, at least twenty-five, at least twenty-six, at least twenty-seven, at least twenty-eight, at least twenty-nine, at least thirty, at least thirty-one, at least thirty-two, at least thirty-three, at least thirty-four, at least thirty-five, at least thirty-six, at least thirty-seven, at least thirty-eight, at least thirty-nine, at least forty, at least forty-one, at least forty-two, at least forty-three, at least forty-four, at least forty-five, at least forty-six, at least forty-seven, at least forty-eight, at least forty-nine, at least fifty, at least fifty-one, at least fifty-two, at least fifty-three, at least fifty-four, at least fifty-five, at least fifty-six, at least fifty-seven, at least fifty-eight, at least fifty- nine, at least sixty, at least sixty-one, at least sixty-two, at least sixty-three, at least sixty-four, at least sixty-five, at least sixty-six, at least sixty-seven, at least sixty-eight, at least sixty-nine, at least seventy, at least seventy-one, or at least seventy-two mutations selected from the group consisting of T472I, I562F, V565D, I570T, I570S, A589V, K608R, L625S, E627K, R629G, E630G, M631I, M631V, T638P, V647A, V647I, K652T, R653K, R654L, R654I, R654H, I670T, G676G, G687R, T703P, K710E, Q716R, T740A, K742E, G752R, R753G, N767D, Q771H, K775R, K789E, E790A, I795L, K797N, N803S, T804A, N808D, K848N, K866R, V875I, K890E, K890N, V922A, K948E, K959N, N990S, T995S, K1014N, V1015A, Y1016C, Y1016S, M1021L, G1030R, Y1036H, Y1036D, I1055E, I1057S, I1057T, R1114G, D1127A, D1127G, D1135N, K1156E, K1156N, N1177S, D1180E, A1184T, N1234D, K1246E, D1251G, N1252D, N1286H, P1301S, D1332N, D1332G, R1335Q, S1338T, I1348V, S1349R, G1367E, G1367T, G1367fs?, and D1368D of the amino acid sequence provided in SEQ ID NO: 2, or in a corresponding mutation, or mutations, in another Cas9 sequence (e.g., any of the sequences of SEQ ID NOs: 2, 4, or 6-11), wherein X represents any amino acid.

[00171] In some embodiments, the amino acid sequence of the Cas9 protein comprises at least one, at least two, at least three, at least four, at least five, at least six, at least seven, at least eight, at least nine, at least ten, at least eleven, at least twelve, at least thirteen, at least fourteen, at least fifteen, at least sixteen, at least seventeen, at least eighteen, at least nineteen, at least twenty, at least twenty-one, at least twenty-two, at least twenty-three, at least twenty-four, at least twenty-five, at least twenty-six, at least twenty-seven, at least twenty-eight, at least twenty-nine, at least thirty, at least thirty-one, at least thirty-two, at least thirty-three, at least thirty-four, at least thirty-five, at least thirty-six, at least thirty-seven, at least thirty-eight, at least thirty-nine, at least forty, at least forty-one, at least forty-two, at least forty-three, at least forty-four, at least forty-five, at least forty-six, at least forty-seven, or at least forty-eight mutations selected from the group consisting of 575, 596, 631, 649, 654, 664, 710, 740, 743, 748, 750, 753, 765, 790, 797, 853, 922, 955, 961, 985, 1012, 1049, 1057, 1114, 1131, 1135, 1150, 1156, 1162, 1180, 1191, 1218, 1219, 1221, 1227, 1249, 1253, 1256, 1286, 1293, 1308, 1317, 1320, 1321, 1332, 1335, and 1339 of the amino acid sequence provided in SEQ ID NO: 2, or in a corresponding mutation, or mutations, in another Cas9 sequence (e.g., any of the sequences of SEQ ID NOs: 2, 4, or 6-11), wherein X represents any amino acid. [00172] In some embodiments, the amino acid sequence of the Cas9 protein comprises at least one, at least two, at least three, at least four, at least five, at least six, at least seven, at least eight, at least nine, at least ten, at least eleven, at least twelve, at least thirteen, at least fourteen, at least fifteen, at least sixteen, at least seventeen, at least eighteen, at least nineteen, at least twenty, at least twenty-one, at least twenty-two, at least twenty-three, at least twenty-four, at least twenty-five, at least twenty-six, at least twenty-seven, at least twenty-eight, at least twenty-nine, at least thirty, at least thirty-one, at least thirty-two, at least thirty-three, at least thirty-four, at least thirty-five, at least thirty-six, at least thirty-seven, at least thirty-eight, at least thirty-nine, at least forty, at least forty-one, at least forty-two, at least forty-three, at least forty-four, at least forty-five, at least forty-six, at least forty-seven, or at least forty-eight mutations selected from the group consisting of X575S, X596Y, X631L, X649R, X654L, X664K, X710E, X740A, X743I, X748I, X750A, X753G, X765X, X790A, X797E, X853E, X922A, X955L, X961E, X985Y, X1012A, X1049G, X1057V, X1114G, X1131C, X1135N, X1150V, X1156E, X1162A, X1180G, X1180A, X1191N, X1218S, X1219V, X1221H, X1227V, X1249S, X1253K, X1256R, X1286K, X1293T, X1308D, X1317K, X1320V, X1321S, X1332G, X1335L, and X1339I of the amino acid sequence provided in SEQ ID NO: 2, or in a corresponding mutation, or mutations, in another Cas9 sequence (e.g., any of the sequences of SEQ ID NOs: 2, 4, or 6-11), wherein X represents any amino acid.

[00173] In some embodiments, the amino acid sequence of the Cas9 protein comprises at least one, at least two, at least three, at least four, at least five, at least six, at least seven, at least eight, at least nine, at least ten, at least eleven, at least twelve, at least thirteen, at least fourteen, at least fifteen, at least sixteen, at least seventeen, at least eighteen, at least nineteen, at least twenty, at least twenty-one, at least twenty-two, at least twenty-three, at least twenty-four, at least twenty-five, at least twenty-six, at least twenty-seven, at least twenty-eight, at least twenty-nine, at least thirty, at least thirty-one, at least thirty-two, at least thirty-three, at least thirty-four, at least thirty-five, at least thirty-six, at least thirty-seven, at least thirty-eight, at least thirty-nine, at least forty, at least forty-one, at least forty-two, at least forty-three, at least forty-four, at least forty-five, at least forty-six, at least forty-seven, or at least forty-eight mutations selected from the group consisting of F575S, D596Y, M631L, K649R, R654L, R664K, K710E, T740A, V743I, V748I, V750A, R753G, R765X, E790A, K797E, D853E, V922A, V955L, K961E, H985Y, D1012A, E1049G, I1057V, R1114G, Y1131C, D1135N, E1150V, K1156E, E1162A, D1180G, D1180A, K1191N, G1218S, E1219V, Q1221H, A1227V, P1249S, E1253K, Q1256R, N1286K, A1293T, N1308D, N1317K, A1320V, P1321S, D1332G, R1335L, and T1339I of the amino acid sequence provided in SEQ ID NO: 2, or in a corresponding mutation, or mutations, in another Cas9 sequence (e.g., any of the sequences of SEQ ID NOs: 2, 4, or 6-11), wherein X represents any amino acid.

[00174] In some embodiments, the amino acid sequence of the Cas9 protein comprises at least one, at least two, at least three, at least four, at least five, at least six, at least seven, at least eight, at least nine, at least ten, at least eleven, at least twelve, at least thirteen, at least fourteen, at least fifteen, at least sixteen, at least seventeen, at least eighteen, at least nineteen, at least twenty, at least twenty-one, at least twenty-two, at least twenty-three, at least twenty-four, at least twenty-five, at least twenty-six, at least twenty-seven, at least twenty-eight, at least twenty-nine, at least thirty, at least thirty-one, at least thirty-two, at least thirty-three, at least thirty-four, at least thirty-five, at least thirty-six, at least thirty-seven, at least thirty-eight, at least thirty-nine, at least forty, at least forty-one, at least forty-two, or at least forty-three mutations selected from the group consisting of 575, 596, 631, 649, 664, 710, 740, 743, 748, 750, 753, 765, 790, 797, 853, 922, 961, 985, 1012, 1049, 1057, 1114, 1131, 1135, 1150, 1156, 1162, 1180, 1191, 1218, 1221, 1249, 1253, 1286, 1293, 1308, 1317, 1320, 1321, 1332, 1335, and 1339 of the amino acid sequence provided in SEQ ID NO: 2, or in a corresponding mutation, or mutations, in another Cas9 sequence (e.g., any of the sequences of SEQ ID NOs: 2, 4, or 6-11), wherein X represents any amino acid.

[00175] In some embodiments, the amino acid sequence of the Cas9 protein comprises at least one, at least two, at least three, at least four, at least five, at least six, at least seven, at least eight, at least nine, at least ten, at least eleven, at least twelve, at least thirteen, at least fourteen, at least fifteen, at least sixteen, at least seventeen, at least eighteen, at least nineteen, at least twenty, at least twenty-one, at least twenty-two, at least twenty-three, at least twenty-four, at least twenty-five, at least twenty-six, at least twenty-seven, at least twenty-eight, at least twenty-nine, at least thirty, at least thirty-one, at least thirty-two, at least thirty-three, at least thirty-four, at least thirty-five, at least thirty-six, at least thirty-seven, at least thirty-eight, at least thirty-nine, at least forty, at least forty-one, at least forty-two, or at least forty-three mutations selected from the group consisting of X575S , X596Y, X631L, X649R, X664K, X710E, X740A, X743I, X748I, X750A, X753G, X765X, X790A, X797E, X853E, X922A, X961E, X985Y, X1012A, X1049G, X1057V, X1114G, X1131C, X1135N, X1150V, X1156E, X1162A, X1180G, X1180A, X1191N, X1218S, X1221H, X1249S, X1253K, X1286K, X1293T, X1308D, X1317K, X1320V, X1321S, X1332G, X1335L, and X1339I of the amino acid sequence provided in SEQ ID NO: 2, or in a corresponding mutation, or mutations, in another Cas9 sequence (e.g., any of the sequences of SEQ ID NOs: 2, 4, or 6-11), wherein X represents any amino acid.

[00176] In some embodiments, the amino acid sequence of the Cas9 protein comprises at least one, at least two, at least three, at least four, at least five, at least six, at least seven, at least eight, at least nine, at least ten, at least eleven, at least twelve, at least thirteen, at least fourteen, at least fifteen, at least sixteen, at least seventeen, at least eighteen, at least nineteen, at least twenty, at least twenty-one, at least twenty-two, at least twenty-three, at least twenty-four, at least twenty-five, at least twenty-six, at least twenty-seven, at least twenty-eight, at least twenty-nine, at least thirty, at least thirty-one, at least thirty-two, at least thirty-three, at least thirty-four, at least thirty-five, at least thirty-six, at least thirty-seven, at least thirty-eight, at least thirty-nine, at least forty, at least forty-one, at least forty-two, or at least forty-three mutations selected from the group consisting of F575S, D596Y, M631L, K649R, R664K, K710E, T740A, V743I, V748I, V750A, R753G, R765X, E790A, K797E, D853E, V922A, K961E, H985Y, D1012A, E1049G, I1057V, R1114G, Y1131C, D1135N, E1150V, K1156E, E1162A, D1180G, D1180A, K1191N, G1218S, Q1221H, P1249S, E1253K, N1286K, A1293T, N1308D, N1317K, A1320V, P1321S, D1332G, R1335L, and T1339I of the amino acid sequence provided in SEQ ID NO: 2, or in a corresponding mutation, or mutations, in another Cas9 sequence (e.g., any of the sequences of SEQ ID NOs: 2, 4, or 6-11), wherein X represents any amino acid.

[00177] In some embodiments, the amino acid sequence of the Cas9 protein comprises an X570T mutation in the amino acid sequence provided in SEQ ID NO: 2, or a corresponding mutation in another Cas9 sequence, wherein X represents any amino acid. In some embodiments, the mutation is X570S.

[00178] In some embodiments, the amino acid sequence of the Cas9 domain comprises an I570T mutation in the amino acid sequence provided in SEQ ID NO: 2, or a corresponding mutation in another Cas9 sequence. In some embodiments, the mutation is I570S.

[00179] In some embodiments, the amino acid sequence of the Cas9 protein comprises an X589S mutation in the amino acid sequence provided in SEQ ID NO: 2, or a corresponding mutation in another Cas9 sequence, wherein X represents any amino acid. In some embodiments, the mutation is X589V.

[00180] In some embodiments, the amino acid sequence of the Cas9 domain comprises an A589S mutation in the amino acid sequence provided in SEQ ID NO: 2, or a corresponding mutation in another Cas9 sequence. In some embodiments, the mutation is A589V.

[00181] In some embodiments, the amino acid sequence of the Cas9 protein comprises an X630G mutation in the amino acid sequence provided in SEQ ID NO: 2, or a corresponding mutation in another Cas9 sequence, wherein X represents any amino acid. In some embodiments, the mutation is X630K.

[00182] In some embodiments, the amino acid sequence of the Cas9 domain comprises an E630G mutation in the amino acid sequence provided in SEQ ID NO: 2, or a corresponding mutation in another Cas9 sequence. In some embodiments, the mutation is E630K. [00183] In some embodiments, the amino acid sequence of the Cas9 protein comprises an X631A mutation in the amino acid sequence provided in SEQ ID NO: 2, or a corresponding mutation in another Cas9 sequence 2, wherein X represents any amino acid. In some embodiments, the mutation is X631I. In some embodiments, the mutation is X631L. In some embodiments, the mutation is X631V.

[00184] In some embodiments, the amino acid sequence of the Cas9 domain comprises an M631A mutation in the amino acid sequence provided in SEQ ID NO: 2, or a corresponding mutation in another Cas9 sequence. In some embodiments, the mutation is M631I. In some embodiments, the mutation is M631L. In some embodiments, the mutation is M631V.

[00185] In some embodiments, the amino acid sequence of the Cas9 protein comprises an X647A mutation in the amino acid sequence provided in SEQ ID NO: 2, or a corresponding mutation in another Cas9 sequence, wherein X represents any amino acid. In some embodiments, the mutation is X647I.

[00186] In some embodiments, the amino acid sequence of the Cas9 domain comprises an V647A mutation in the amino acid sequence provided in SEQ ID NO: 2, or a corresponding mutation in another Cas9 sequence. In some embodiments, the mutation is V647I.

[00187] In some embodiments, the amino acid sequence of the Cas9 protein comprises an X654H mutation in the amino acid sequence provided in SEQ ID NO: 2, or a corresponding mutation in another Cas9 sequence, wherein X represents any amino acid. In some embodiments, the mutation is X654I. In some embodiments, the mutation is X654L.

[00188] In some embodiments, the amino acid sequence of the Cas9 domain comprises an R654H mutation in the amino acid sequence provided in SEQ ID NO: 2, or a corresponding mutation in another Cas9 sequence. In some embodiments, the mutation is R654I. In some embodiments, the mutation is R654L. [00189] In some embodiments, the amino acid sequence of the Cas9 protein comprises an X890E mutation in the amino acid sequence provided in SEQ ID NO: 2, or a corresponding mutation in another Cas9 sequence, wherein X represents any amino acid. In some embodiments, the mutation is X890N.

[00190] In some embodiments, the amino acid sequence of the Cas9 domain comprises a K890E mutation in the amino acid sequence provided in SEQ ID NO: 2, or a corresponding mutation in another Cas9 sequence. In some embodiments, the mutation is K890N.

[00191] In some embodiments, the amino acid sequence of the Cas9 protein comprises an X1016C mutation in the amino acid sequence provided in SEQ ID NO: 2, or a corresponding mutation in another Cas9 sequence, wherein X represents any amino acid. In some embodiments, the mutation is X1016D. In some embodiments, the mutation is X1016S.

[00192] In some embodiments, the amino acid sequence of the Cas9 domain comprises an Y1016C mutation in the amino acid sequence provided in SEQ ID NO: 2, or a corresponding mutation in another Cas9 sequence. In some embodiments, the mutation is Y1016D. In some embodiments, the mutation is Y1016S.

[00193] In some embodiments, the amino acid sequence of the Cas9 protein comprises an X1021L mutation in the amino acid sequence provided in SEQ ID NO: 2, or a corresponding mutation in another Cas9 sequence, wherein X represents any amino acid. In some embodiments, the mutation is X1021T.

[00194] In some embodiments, the amino acid sequence of the Cas9 domain comprises an M1021L mutation in the amino acid sequence provided in SEQ ID NO: 2, or a corresponding mutation in another Cas9 sequence. In some embodiments, the mutation is M1021T.

[00195] In some embodiments, the amino acid sequence of the Cas9 protein comprises an X1036D mutation in the amino acid sequence provided in SEQ ID NO: 2, or a corresponding mutation in another Cas9 sequence, wherein X represents any amino acid. In some embodiments, the mutation is X1036H.

[00196] In some embodiments, the amino acid sequence of the Cas9 domain comprises an Y1036D mutation in the amino acid sequence provided in SEQ ID NO: 2, or a corresponding mutation in another Cas9 sequence. In some embodiments, the mutation is Y1036H.

[00197] In some embodiments, the amino acid sequence of the Cas9 protein comprises an X1057S mutation in the amino acid sequence provided in SEQ ID NO: 2, or a corresponding mutation in another Cas9 sequence, wherein X represents any amino acid. In some embodiments, the mutation is X1057T. In some embodiments, the mutation is X1057V.

[00198] In some embodiments, the amino acid sequence of the Cas9 domain comprises an I1057S mutation in the amino acid sequence provided in SEQ ID NO: 2, or a corresponding mutation in another Cas9 sequence. In some embodiments, the mutation is I1057T. In some embodiments, the mutation is X1057V.

[00199] In some embodiments, the amino acid sequence of the Cas9 protein comprises an X1127A mutation in the amino acid sequence provided in SEQ ID NO: 2, or a corresponding mutation in another Cas9 sequence, wherein X represents any amino acid. In some embodiments, the mutation is X1121G.

[00200] In some embodiments, the amino acid sequence of the Cas9 domain comprises an D1127A mutation in the amino acid sequence provided in SEQ ID NO: 2, or a corresponding mutation in another Cas9 sequence. In some embodiments, the mutation is D1127G.

[00201] In some embodiments, the amino acid sequence of the Cas9 protein comprises an X1156E mutation in the amino acid sequence provided in SEQ ID NO: 2, or a corresponding mutation in another Cas9 sequence, wherein X represents any amino acid. In some embodiments, the mutation is X1156N. [00202] In some embodiments, the amino acid sequence of the Cas9 domain comprises an K1156E mutation in the amino acid sequence provided in SEQ ID NO: 2, or a corresponding mutation in another Cas9 sequence. In some embodiments, the mutation is K1156N.

[00203] In some embodiments, the amino acid sequence of the Cas9 protein comprises an X1180E mutation in the amino acid sequence provided in SEQ ID NO: 2, or a corresponding mutation in another Cas9 sequence, wherein X represents any amino acid. In some embodiments, the mutation is X1180G.

[00204] In some embodiments, the amino acid sequence of the Cas9 domain comprises an D1180E mutation in the amino acid sequence provided in SEQ ID NO: 2, or a corresponding mutation in another Cas9 sequence. In some embodiments, the mutation is D1180G.

[00205] In some embodiments, the amino acid sequence of the Cas9 protein comprises an X1286H mutation in the amino acid sequence provided in SEQ ID NO: 2, or a corresponding mutation in another Cas9 sequence, wherein X represents any amino acid. In some embodiments, the mutation is X1286K.

[00206] In some embodiments, the amino acid sequence of the Cas9 domain comprises an N1286H mutation in the amino acid sequence provided in SEQ ID NO: 2, or a corresponding mutation in another Cas9 sequence. In some embodiments, the mutation is N1286K.

[00207] In some embodiments, the amino acid sequence of the Cas9 protein comprises an X1132G mutation in the amino acid sequence provided in SEQ ID NO: 2, or a corresponding mutation in another Cas9 sequence, wherein X represents any amino acid. In some embodiments, the mutation is X1132N.

[00208] In some embodiments, the amino acid sequence of the Cas9 domain comprises an D1132G mutation in the amino acid sequence provided in SEQ ID NO: 2, or a corresponding mutation in another Cas9 sequence. In some embodiments, the mutation is D1132N. [00209] In some embodiments, the amino acid sequence of the Cas9 protein comprises an X1335L mutation in the amino acid sequence provided in SEQ ID NO: 2, or a corresponding mutation in another Cas9 sequence, wherein X represents any amino acid. In some embodiments, the mutation is X1335Q.

[00210] In some embodiments, the amino acid sequence of the Cas9 domain comprises an R1335L mutation in the amino acid sequence provided in SEQ ID NO: 2, or a corresponding mutation in another Cas9 sequence. In some embodiments, the mutation is R1335Q.

[00211] In some embodiments, the Cas9 protein comprises a combination of mutations that exhibit activity on a target sequence comprising a 5´-NAA-3´ PAM sequence at its 3’-end. In some embodiments, the combination of mutations are present in any one of the clones listed in Table 1. In some embodiments, the combination of mutations are conservative mutations of the clones listed in Table 1. In some embodiments, the Cas9 protein comprises the combination of mutations of any one of the Cas9 clones listed in Table 1. In some embodiments, the Cas9 protein comprises the combination of mutations present in any one of the Cas9 clones selected from the group consisting of N3.19.4c-3; N3.19.4c-4; P4.2-72-4; P4.2-72-5; P10.6.144.2; P10.5.192.7; P10.5.192.10;

P10.6.144.5; P10.6.192.1; P10.6.192.9; P10.6.192.12; P13.2-8; P13.3-3; P13.4-3; P16.2-120-1; P16.2-120-2; P16.2-120-3; P16.2-120-4; P16.2-120-5; P16.2-120-6; P16.1-3; P16.3-2; P16.4-5(es); and P16.6-2. In some embodiments, the Cas9 protein comprises the combination of mutations present in any one of the Cas9 clones selected from the group consisting of N3.19.4c-3; N3.19.4c-4; P4.2-72- 4; P4.2-72-5; P10.6.144.2; P10.5.192.7; P10.5.192.10; P10.6.144.5; P10.6.192.1; P10.6.192.9;

P10.6.192.12; P13.2-8; P13.3-3; P13.4-3; P16.2-120-1; P16.2-120-2; P16.2-120-3; P16.2-120-4; P16.2-120-5; P16.2-120-6; P16.1-3; P16.3-2; P16.4-5(es); and P16.6-2, or a combination of conservative mutations thereto.

[00212] Table 1: NAA PAM Clones

[00213] In some embodiments, the Cas9 protein comprises an amino acid sequence that is at least 80% identical to the amino acid sequence of a Cas9 protein as provided by any one of the variants of Table 1. In some embodiments, the Cas9 protein comprises an amino acid sequence that is at least 85%, at least 90%, at least 92%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or at least 99.5% identical to the amino acid sequence of a Cas9 protein as provided by any one of the variants of Table 1.

[00214] In some embodiments, the Cas9 protein exhibits an increased activity on a target sequence that does not comprise the canonical PAM (5´-NGG-3´) at its 3’ end as compared to Streptococcus pyogenes Cas9 as provided by SEQ ID NO: 2. In some embodiments, the Cas9 protein exhibits an activity on a target sequence having a 3’ end that is not directly adjacent to the canonical PAM sequence (5´-NGG-3´) that is at least 5-fold increased as compared to the activity of Streptococcus pyogenes Cas9 as provided by SEQ ID NO: 2 on the same target sequence. In some embodiments, the Cas9 protein exhibits an activity on a target sequence that is not directly adjacent to the canonical PAM sequence (5´-NGG-3´) that is at least 10-fold, at least 50-fold, at least 100-fold, at least 500- fold, at least 1,000-fold, at least 5,000-fold, at least 10,000-fold, at least 50,000-fold, at least 100,000- fold, at least 500,000-fold, or at least 1,000,000-fold increased as compared to the activity of Streptococcus pyogenes as provided by SEQ ID NO: 2 on the same target sequence. In some embodiments, the 3’ end of the target sequence is directly adjacent to an AAA, GAA, CAA, or TAA sequence.

[00215] In some embodiments, the Cas9 protein comprises a combination of mutations that exhibit activity on a target sequence comprising a 5´-NAC-3´ PAM sequence at its 3’-end. In some embodiments, the combination of mutations are present in any one of the clones listed in Table 2. In some embodiments, the combination of mutations are conservative mutations of the clones listed in Table 2. In some embodiments, the Cas9 protein comprises the combination of mutations of any one of the Cas9 clones listed in Table 2. In some embodiments, the Cas9 protein comprises the combination of mutations present in any one of the Cas9 clones selected from the group consisting of N4.CAC-1; N4.CAC-5; N4.CAC06; SacB.CAC.4h; N3.CAC-1; N3.CAC-5; N3.CAC-6; N3.CAC-8; P15.1.166-3; P15.1.166-8; P15.2.166-2; P15.3.166-4; P15.3.166-5; P15.3.166-7; P15.4.166-4; P15.4.166-8; P17.1.144-1; P17.1.144-2; P17.1.144-3; P17.1.144-4; P17.1.144-5; P17.1.144-7; P17.1.144-8; P17.2.144-1; P17.2.144-2; P17.2.144-3; P17.2.144-4; P17.2.144-5; P17.2.144-6; P17.2.144-7; P17.2.144-8; P17.1-1; P17.1-5; and P17.1.7-4(fn). In some embodiments, the Cas9 protein comprises the combination of mutations present in any one of the Cas9 clones selected from the group consisting of N4.CAC-1; N4.CAC-5; N4.CAC06; SacB.CAC.4h; N3.CAC-1; N3.CAC-5; N3.CAC-6; N3.CAC-8; P15.1.166-3; P15.1.166-8; P15.2.166-2; P15.3.166-4; P15.3.166-5;

P15.3.166-7; P15.4.166-4; P15.4.166-8; P17.1.144-1; P17.1.144-2; P17.1.144-3; P17.1.144-4; P17.1.144-5; P17.1.144-7; P17.1.144-8; P17.2.144-1; P17.2.144-2; P17.2.144-3; P17.2.144-4; P17.2.144-5; P17.2.144-6; P17.2.144-7; P17.2.144-8; P17.1-1; P17.1-5; and P17.1.7-4(fn), or a combination of conservative mutations thereto.

[00216] Table 2: NAC PAM Clones

[00217] In some embodiments, the Cas9 protein comprises an amino acid sequence that is at least 80% identical to the amino acid sequence of a Cas9 protein as provided by any one of the variants of Table 2. In some embodiments, the Cas9 protein comprises an amino acid sequence that is at least 85%, at least 90%, at least 92%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or at least 99.5% identical to the amino acid sequence of a Cas9 protein as provided by any one of the variants of Table 2.

[00218] In some embodiments, the Cas9 protein exhibits an increased activity on a target sequence that does not comprise the canonical PAM (5´-NGG-3´) at its 3’ end as compared to Streptococcus pyogenes Cas9 as provided by SEQ ID NO: 2. In some embodiments, the Cas9 protein exhibits an activity on a target sequence having a 3’ end that is not directly adjacent to the canonical PAM sequence (5´-NGG-3´) that is at least 5-fold increased as compared to the activity of Streptococcus pyogenes Cas9 as provided by SEQ ID NO: 2 on the same target sequence. In some embodiments, the Cas9 protein exhibits an activity on a target sequence that is not directly adjacent to the canonical PAM sequence (5´-NGG-3´) that is at least 10-fold, at least 50-fold, at least 100-fold, at least 500- fold, at least 1,000-fold, at least 5,000-fold, at least 10,000-fold, at least 50,000-fold, at least 100,000- fold, at least 500,000-fold, or at least 1,000,000-fold increased as compared to the activity of Streptococcus pyogenes as provided by SEQ ID NO: 2 on the same target sequence. In some embodiments, the 3’ end of the target sequence is directly adjacent to an AAC, GAC, CAC, or TAC sequence.

[00219] In some embodiments, the Cas9 protein comprises a combination of mutations that exhibit activity on a target sequence comprising a 5´-NAT-3´ PAM sequence at its 3’-end. In some embodiments, the combination of mutations are present in any one of the clones listed in Table 3. In some embodiments, the combination of mutations are conservative mutations of the clones listed in Table 3. In some embodiments, the Cas9 protein comprises the combination of mutations of any one of the Cas9 clones listed in Table 3. In some embodiments, the Cas9 protein comprises the combination of mutations present in any one of the Cas9 clones selected from the group consisting of SacB.N4.19.TAT-4h-1; SacB.N4.19.TAT-4h-3; P12.2.b9-8; P12.3.b9-8; P12.3.b9-8 (ax); P12.3.b10- 6; SacB.P12a2.AAT.3hr.maj; SacB.P12a2.AAT.3hr.min; P17.4-1; P17.4-2; P17.4-3; P17.4-4;

P17.4-5; P17.4-6; P17.4-8; P17-4-1-1; P17-4-3-1; and P17-4-6-1. In some embodiments, the Cas9 protein comprises the combination of mutations present in any one of the Cas9 clones selected from the group consisting of SacB.N4.19.TAT-4h-1; SacB.N4.19.TAT-4h-3; P12.2.b9-8; P12.3.b9-8; P12.3.b9-8 (ax); P12.3.b10-6; SacB.P12a2.AAT.3hr.maj; SacB.P12a2.AAT.3hr.min; P17.4-1; P17.4- 2; P17.4-3; P17.4-4; P17.4-5; P17.4-6; P17.4-8; P17-4-1-1; P17-4-3-1; and P17-4-6-1, or a combination of conservative mutations thereto.

[00220] Table 3: NAT PAM Clones

[00221] In some embodiments, the Cas9 protein comprises an amino acid sequence that is at least 80% identical to the amino acid sequence of a Cas9 protein as provided by any one of the variants of Table 3. In some embodiments, the Cas9 protein comprises an amino acid sequence that is at least 85%, at least 90%, at least 92%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or at least 99.5% identical to the amino acid sequence of a Cas9 protein as provided by any one of the variants of Table 3.

Cas9 Activity

[00222] In some embodiments, the Cas9 protein exhibits an increased activity on a target sequence that does not comprise the canonical PAM (5´-NGG-3´) at its 3’ end as compared to Streptococcus pyogenes Cas9 as provided by SEQ ID NO: 2. In some embodiments, the Ca9 protein exhibits an activity on a target sequence having a 3’ end that is not directly adjacent to the canonical PAM sequence (5´-NGG-3´) that is at least 5-fold increased as compared to the activity of Streptococcus pyogenes Cas9 as provided by SEQ ID NO: 2 on the same target sequence. In some embodiments, the Cas9 protein exhibits an activity on a target sequence that is not directly adjacent to the canonical PAM sequence (5´-NGG-3´) that is at least 10-fold, at least 50-fold, at least 100-fold, at least 500- fold, at least 1,000-fold, at least 5,000-fold, at least 10,000-fold, at least 50,000-fold, at least 100,000- fold, at least 500,000-fold, or at least 1,000,000-fold increased as compared to the activity of

Streptococcus pyogenes as provided by SEQ ID NO: 2 on the same target sequence. In some embodiments, the 3’ end of the target sequence is directly adjacent to an AAT, GAT, CAT, or TAT sequence.

[00223] In some embodiments, the Cas9 domain exhibits activity on a target sequence having a 3ʹ- end that is not directly adjacent to the canonical PAM sequence (5¢-NGG-3¢), or on a target sequence that does not comprise the canonical PAM sequence (5¢-NGG-3¢), that is at least 2-fold, at least 3-fold, at least 4-fold, at least 5-fold, at least 10-fold, at least 50-fold, at least 100-fold, at least 500-fold, at least 1,000-fold, at least 5,000-fold, at least 10,000-fold, at least 50,000-fold, at least 100,000-fold, at least 500,000-fold, or at least 1,000,000-fold increased as compared to the activity of Streptococcus pyogenes Cas9 as provided by SEQ ID NO: 2 on the same target sequence. In some embodiments, the Cas9 domain exhibits activity on a target sequence having a 3ʹ-end that is not directly adjacent to the canonical PAM sequence (5¢-NGG-3¢), or on a target sequence that does not comprise the canonical PAM sequence (5¢-NGG-3¢), that is at least 10%, at least 15%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, or at least 90% greater than the activity of Streptococcus pyogenes Cas9 as provided by SEQ ID NO: 2 on the same target sequence. In some embodiments, the 3ʹ-end of the target sequence is directly adjacent to an NGT, NGA, NGC, and NNG sequence, wherein N is A, G, T, or C. In some embodiments, the 3ʹ-end of the target sequence is directly adjacent to an AAA, AAC, AAG, AAT, CAA, CAC, CAG, CAT, GAA, GAC, GAG, GAT, TAA, TAC, TAG, TAT, ACA, ACC, ACG, ACT, CCA, CCC, CCG, CCT, GCA, GCC, GCG, GCT, TCA, TCC, TCG, TCT, AGA, AGC, AGT, CGA, CGC, CGT, GGA, GGC, GGT, TGA, TGC, TGT, ATA, ATC, ATG, ATT, CTA, CTC, CTG, CTT, GTA, GTC, GTG, GTT, TTA, TTC, TTG, or TTT PAM sequence. In some embodiments, the 3ʹ-end of the target sequence is directly adjacent to an CGG, AGT, TGG, AGT, CGT, GGG, CGT, TGT, GGT, AGC, CGC, TGC, GGC, AGA, CGA, TGA, GGA, GAA, GAT, or CAA sequence. In some embodiments, the Cas9 domain activity is measured by a nuclease assay, a deamination assay, a transcriptional activation assay, a binding assay, or by PCR or sequencing. In some embodiments, the transcriptional activation assay is a reporter activation assay, such as a GFP activation assay. Exemplary methods for measuring binding activity (e.g., of Cas9) using transcriptional activation assays are known in the art and would be apparent to the skilled artisan. For example, methods for measuring Cas9 activity using the tripartite activator VPR have been described in Chavez A., et al.,“Highly efficient Cas9-mediated transcriptional programming.” Nature Methods 12, 326–328 (2015), the entire contents of which are incorporated by reference herein.

[00224] In some embodiments, the Cas9 domain is mutated with respect to a corresponding wild- type protein such that the mutated Cas9 domain lacks the ability to cleave one or both strands of a target polynucleotide containing a target sequence. In particular embodiments, an aspartate-to- alanine substitution (D10A) in the RuvC1 catalytic domain of S. pyogenes Cas9 converts Cas9 from a nuclease that cleaves both strands to a nickase that nicks the targeted strand, or the strand that is complementary to the gRNA. A histidine-to-alanine substitution (H840A) in the HNH catalytic domain of S. pyogenes Cas9 generates a nick on the strand that is displaced by the gRNA during strand invasion, also referred to herein as the non-edited strand. The single catalytically active nuclease site of the nCas9 leaves a nick in the non-edited strand, which will direct mismatch repair machinery to read (rather than remove) the modified base during repair (i.e., a substituted guanine or guanine derivative at the target site). Other examples of mutations that render Cas9 a nickase include, without limitation, N854A and N863A in SpCas9, and corresponding mutations in other wild- type Cas9 proteins or variants thereof. Reference is made to U.S. Patent No.8,945,839, incorporated herein by reference.

[00225] In some embodiments, the amino acid sequence of the HNH domain is at least 80%, at least 85%, at least 90%, at least 92%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or at least 99.5% identical to the amino acid sequence of the HNH domain of any of SEQ ID NO: 2. In some embodiments, the amino acid sequence of the RuvC domain is at least 80%, at least 85%, at least 90%, at least 92%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or at least 99.5% identical to the amino acid sequence of the RuvC domain of SEQ ID NO: 2. In some embodiments, the Cas9 domain comprises the RuvC and HNH domains of SEQ ID NO: 2. In some embodiments, the Cas9 domain comprises a D10A and/or a H840A mutation in the amino acid sequence provided in SEQ ID NO: 2, or corresponding mutation(s) in another Cas9 sequence.

[00226] In some embodiments, the disclosure provides SpCas9 mutant proteins that work best on NRRH, NRCH, and NRTH PAMs. The SpCas9 mutant protein that works best on NARH (“es” variant), has an amino acid sequence as presented in SEQ ID NO: 22 (underligned residues are mutated from SpCas9)

[00227] The SpCas9 mutant protein that works best on NRCH (“fn” variant), has an amino acid sequence as presented in SEQ ID NO: 23 (underligned residues are mutated from SpCas9)

[00228] The SpCas9 mutant protein that works best on NRTH (“ax” variant), has an amino acid

[00229] Some aspects of the disclosure provide high fidelity Cas9 domains. In some embodiments, high fidelity Cas9 domains have decreased electrostatic interactions between the Cas9 domain and a sugar-phosphate backbone of a DNA, as compared to a wild-type Cas9 domain. In some

embodiments, any of the Cas9 domains provided herein comprise one or more mutations that decrease the association between the Cas9 domain and a sugar-phosphate backbone of a DNA. In some embodiments, any of the Cas9 domains provided herein comprise one or more mutations that decrease the association between the Cas9 domain and a sugar-phosphate backbone of a DNA by at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, or at least 95%. In some embodiments, any of the Cas9 domains provided herein comprise one or more of a N497X, a R661X, a Q695X, and/or a Q926X mutation of the amino acid sequence provided in SEQ ID NO: 135, or a corresponding mutation in another Cas9 sequence, wherein X is any amino acid. In some

embodiments, any of the Cas9 domains provided herein comprise one or more of a N497A, a R661A, a Q695A, and/or a Q926A mutation of the amino acid sequence provided in SEQ ID NO: 135, or a corresponding mutation in another Cas9 sequence. In some embodiments, the Cas9 domain comprises a D10A mutation of the amino acid sequence provided in SEQ ID NO: 135, or a corresponding mutation in another Cas9 sequence. In some embodiments, the Cas9 domain comprises the amino acid sequence as set forth in SEQ ID NO: 135. High fidelity Cas9 domains have been described in the art and would be apparent to the skilled artisan. For example, high fidelity Cas9 domains have been described in Kleinstiver, B.P., et al.“High-fidelity CRISPR-Cas9 nucleases with no detectable genome-wide off-target effects.” Nature 529, 490-495 (2016); and Slaymaker, I.M., et al.“Rationally engineered Cas9 nucleases with improved specificity.” Science 351, 84-88 (2015); the entire contents of each are incorporated herein by reference. It should be appreciated that, based on the present disclosure and knowledge in the art, that mutations in any Cas9 domain may be generated to make high fidelity Cas9 domains that have decreased electrostatic interactions between the Cas9 domain and a sugar-phosphate backbone of a DNA, as compared to a wild-type Cas9 domain.

[00230] Cas9 domain where mutations relative to Cas9 of SEQ ID NO: 6 are shown in bold and underlines.

[00231] In some embodiments, the Cas9 domain of any of the fusion proteins provided herein comprises an amino acid sequence that is at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or at least 99.5% identical to the amino acid set forth as SEQ ID NO: 10 (S. aureus Cas9), below. In some embodiments, the Cas9 domain of any of the fusion proteins provided herein comprises the amino acid sequence of SEQ ID NO: 10. In some embodiments, the Cas9 domain of any of the fusion proteins provided herein consists of the amino acid sequence of SEQ ID NO: 10.

[00232] An exemplary SaCas9 amino acid sequence is:

[00233] An additional Cas9 domain with altered PAM specificity, such as a domain having at least 80%, at least 85%, at least 90%, at least 95%, or at least 99% sequence identity with wild type Geobacillus thermodenitrificans Cas9 (SEQ ID NO: 11, GeoCas9) may be used.

[00234] In some embodiments, a Cas9 domain refers to a Cas9 or Cas9 homolog from archaea (e.g., nanoarchaea), which constitute a domain and kingdom of single-celled prokaryotic microbes. In some embodiments, a Cas9 domain may comprise a CasX (now referred to as Cas12e) or CasY (now referred to as Cas12d) omain, which have been described in, for example, Burstein et al.,“New CRISPR–Cas systems from uncultivated microbes.” Cell Res.2017 Feb 21. doi: 10.1038/cr.2017.21, and Liu et al.,“CasX enzymes comprise a distinct family of RNA-guided genome editors,” Nature. 2019; 566(7743):218-223, each of which is incorporated herein by reference. Using genome- resolved metagenomics, a number of CRISPR–Cas systems were identified, including the first reported Cas9 in the archaeal domain of life. This divergent Cas9 protein was found in little-studied nanoarchaea as part of an active CRISPR–Cas system. In bacteria, two previously unknown systems were discovered, CRISPR–CasX and CRISPR–CasY, which are among the most compact systems yet discovered. In some embodiments, napDNAbp domain refers to CasX, or a variant of CasX. In some embodiments, napDNAbp domain refers to a CasY, or a variant of CasY. It should be appreciated that other RNA-guided DNA binding proteins may be used as a napDNAbp and are within the scope of this disclosure. In some embodiments, the napDNAbp comprises an amino acid sequence that is at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or at least 99.5% identical to a naturally-occurring CasX or CasY protein.

Cytidine deaminases

[00235] In some embodiments, the deaminase domain is a cytidine deaminase domain. A cytidine deaminase domain may also be referred to interchangeably as a cytosine deaminase domain. In some embodiments, the cytidine deaminase catalyzes the hydrolytic deamination of cytidine (C) or deoxycytidine (dC) to uridine (U) or deoxyuridine (dU), respectively. In some embodiments, the cytidine deaminase domain catalyzes the hydrolytic deamination of cytosine (C) to uracil (U). In some embodiments, the cytidine deaminase catalyzes the hydrolytic deamination of cytidine or cytosine in deoxyribonucleic acid (DNA). Without wishing to be bound by any particular theory, fusion proteins comprising a cytidine deaminase are useful inter alia for targeted editing, referred to herein as“base editing,” of nucleic acid sequences in vitro and in vivo.

[00236] One exemplary suitable type of cytidine deaminase is a cytidine deaminase, for example, of the APOBEC family. The apolipoprotein B mRNA-editing complex (APOBEC) family of cytidine deaminase enzymes encompasses eleven proteins that serve to initiate mutagenesis in a controlled and beneficial manner (see, e.g., Conticello SG. The AID/APOBEC family of nucleic acid mutators. Genome Biol.2008; 9(6):229). One family member, activation-induced cytidine deaminase (AID), is responsible for the maturation of antibodies by converting cytosines in ssDNA to uracils in a transcription-dependent, strand-biased fashion (see, e.g., Reynaud CA, et al. What role for AID: mutator, or assembler of the immunoglobulin mutasome, Nat Immunol.2003; 4(7):631-638). The apolipoprotein B editing complex 3 (APOBEC3) enzyme provides protection to human cells against a certain HIV-1 strain via the deamination of cytosines in reverse-transcribed viral ssDNA (see, e.g., Bhagwat AS. DNA-cytosine deaminases: from antibody maturation to antiviral defense. DNA Repair (Amst).2004; 3(1):85-89). These proteins all require a Zn ²⁺ -coordinating motif (His-X-Glu-X _23-26 -Pro- Cys-X _2-4 -Cys; SEQ ID NO: 405) and bound water molecule for catalytic activity. The Glu residue acts to activate the water molecule to a zinc hydroxide for nucleophilic attack in the deamination reaction. Each family member preferentially deaminates at its own particular“hotspot”, ranging from WRC (W is A or T, R is A or G) for hAID, to TTC for hAPOBEC3F (see, e.g., Navaratnam N and Sarwar R. An overview of cytidine deaminases. Int J Hematol.2006; 83(3):195-200). A recent crystal structure of the catalytic domain of APOBEC3G revealed a secondary structure comprised of a five-stranded b- sheet core flanked by six a-helices, which is believed to be conserved across the entire family (see, e.g., Holden LG, et al. Crystal structure of the anti-viral APOBEC3G catalytic domain and functional implications. Nature.2008; 456(7218):121-4). The active center loops have been shown to be responsible for both ssDNA binding and in determining“hotspot” identity (see, e.g., Chelico L, et al. Biochemical basis of immunological and retroviral responses to DNA-targeted cytosine deamination by activation-induced cytidine deaminase and APOBEC3G. J Biol Chem.2009; 284(41).27761-5). Overexpression of these enzymes has been linked to genomic instability and cancer, thus highlighting the importance of sequence-specific targeting (see, e.g., Pham P, et al. Reward versus risk: DNA cytidine deaminases triggering immunity and disease. Biochemistry.2005; 44(8):2703-15).

[00237] Some aspects of this disclosure relate to the recognition that the activity of cytidine deaminase enzymes such as APOBEC enzymes can be directed to a specific site in genomic DNA. Without wishing to be bound by any particular theory, advantages of using a nucleic acid programmable binding protein (e.g., a Cas9 domain) as a recognition agent include (1) the sequence specificity of nucleic acid programmable binding protein (e.g., a Cas9 domain) can be easily altered by simply changing the sgRNA sequence; and (2) the nucleic acid programmable binding protein (e.g., a Cas9 domain) may bind to its target sequence by denaturing the dsDNA, resulting in a stretch of DNA that is single-stranded and therefore a viable substrate for the deaminase. It should be understood that other catalytic domains of napDNAbps, or catalytic domains from other nucleic acid editing proteins, can also be used to generate fusion proteins with Cas9, and that the disclosure is not limited in this regard.

[00238] In view of the results provided herein regarding the nucleotides that can be targeted by Cas9:deaminase fusion proteins, a person of ordinary skill in the art will be able to design suitable guide RNAs to target the fusion proteins to a target sequence that comprises a nucleotide to be deaminated.

[00239] In some embodiments, the cytidine deaminase is an apolipoprotein B mRNA- editing complex (APOBEC) family deaminase. In some embodiments, the cytidine deaminase is an APOBEC1 deaminase. In some embodiments, the cytidine deaminase is an APOBEC2 deaminase. In some embodiments, the cytidine deaminase is an APOBEC3 deaminase. In some embodiments, the cytidine deaminase is an APOBEC3A deaminase. In some embodiments, the cytidine deaminase is an APOBEC3B deaminase. In some embodiments, the cytidine deaminase is an APOBEC3C deaminase. In some embodiments, the cytidine deaminase is an APOBEC3D deaminase. In some embodiments, the cytidine deaminase is an APOBEC3E deaminase. In some embodiments, the cytidine deaminase is an APOBEC3F deaminase. In some embodiments, the cytidine deaminase is an APOBEC3G deaminase. In some embodiments, the cytidine deaminase is an APOBEC3H deaminase. In some embodiments, the cytidine deaminase is an APOBEC4 deaminase. In some embodiments, the cytidine deaminase is an activation-induced deaminase (AID). In some embodiments, the cytidine deaminase is a vertebrate cytidine deaminase. In some embodiments, the cytidine deaminase is an invertebrate cytidine deaminase. In some embodiments, the cytidine deaminase is a human, chimpanzee, gorilla, monkey, cow, dog, rat, or mouse deaminase. In some embodiments, the cytidine deaminase is a human cytidine deaminase. In some embodiments, the cytidine deaminase is a rat cytidine deaminase, e.g., rAPOBEC1. In some embodiments, the cytidine deaminase is a Petromyzon marinus cytidine deaminase 1 (pmCDA1) (SEQ ID NO: 58). In some embodiments, the cytidine deaminase is a human APOBEC3G (SEQ ID NO: 60). In some embodiments, the cytidine deaminase is a fragment of the human APOBEC3G. In some embodiments, the deaminase is a human APOBEC3G variant comprising a D316R and D317R mutation. In some embodiments, the deaminase is a fragment of the human APOBEC3G and comprising mutations corresponding to the D316R and D317R mutations in SEQ ID NO: 61.

[00240] In some embodiments, the nucleic acid editing domain is at least 80%, at least 85%, at least 90%, at least 92%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or at least 99.5% identical to the cytidine deaminase domain of any one of SEQ ID NOs: 27-61. In some embodiments, the nucleic acid editing domain comprises the amino acid sequence of any one of SEQ ID NOs: 27-61.

[00241] Some exemplary suitable nucleic-acid editing domains, e.g., cytidine deaminases and cytidine deaminase domains, that can be fused to napDNAbps (e.g., Cas9 domains) according to aspects of this disclosure are provided below. It should be understood that, in some embodiments, the active domain of the respective sequence can be used, e.g., the domain without a localizing signal (nuclear localization sequence, without nuclear export signal, cytoplasmic localizing signal).

[00242] Human AID:

(underline: nuclear localization sequence; double underline: nuclear export signal)

[00243] Mouse AID:

(underline: nuclear localization sequence; double underline: nuclear export signal)

[00244] Dog AID:

(underline: nuclear localization sequence; double underline: nuclear export signal)

[00245] Bovine AID:

(underline: nuclear localization sequence; double underline: nuclear export signal)

[00246] Rat AID:

(underline: nuclear localization sequence; double underline: nuclear export signal)

[00247] Mouse APOBEC-3:

[00248] Rat APOBEC-3:

(italic: nucleic acid editing domain)

[00249] Rhesus macaque APOBEC-3G:

(italic: nucleic acid editing domain; underline: cytoplasmic localization signal)

[00250] Chimpanzee APOBEC-3G:

[00251] Green monkey APOBEC-3G:

(SEQ ID NO: 36)

(italic: nucleic acid editing domain; underline: cytoplasmic localization signal)

[00252] Human APOBEC-3G:

(italic: nucleic acid editing domain; underline: cytoplasmic localization signal)

[00253] Human APOBEC-3F:

(SEQ ID NO: 38)

(italic: nucleic acid editing domain)

[00254] Human APOBEC-3B:

[00255] Rat APOBEC-3B:

40)

[00256] Bovine APOBEC-3B:

Adenosine deaminases

[00277] The disclosure provides fusion proteins that comprise one or more adenosine deaminases. In some aspects, such fusion proteins are capable of deaminating adenosine in a nucleic acid sequence (e.g., DNA or RNA). As one example, any of the fusion proteins provided herein may be base editors, (e.g., adenine base editors). Without wishing to be bound by any particular theory, dimerization of adenosine deaminases (e.g., in cis or in trans) may improve the ability (e.g., efficiency) of the fusion protein to modify a nucleic acid base, for example to deaminate adenine. In some embodiments, any of the fusion proteins may comprise 2, 3, 4 or 5 adenosine deaminases. In some embodiments, any of the fusion proteins provided herein comprise two adenosine deaminases. Exemplary, non-limiting, embodiments of adenosine deaminases are provided herein. It should be appreciated that the mutations provided herein (e.g., mutations in ecTadA) may be applied to adenosine deaminases in other adenosine base editors, for example those provided in U.S. Patent Publication No. 2018/0073012, published March 15, 2018, which issued as U.S. Patent No.10,113,163, on October 30, 2018; U.S. Patent Publication No.2017/0121693, published May 4, 2017, which issued as U.S. Patent No.10,167,457 on January 1, 2019; International Publication No. WO 2017/070633, published April 27, 2017; U.S. Patent Publication No.2015/0166980, published June 18, 2015; U.S. Patent No. 9,840,699, issued December 12, 2017; and U.S. Patent No.10,077,453, issued September 18, 2018, all of which are incorporated herein by reference in their entireties.

[00278] In some embodiments, any of the adenosine deaminases provided herein is capable of deaminating adenine. In some embodiments, the adenosine deaminases provided herein are capable of deaminating adenine in a deoxyadenosine residue of DNA. The adenosine deaminase may be derived from any suitable organism (e.g., E. coli). In some embodiments, the adenosine deaminase is a naturally-occurring adenosine deaminase that includes one or more mutations corresponding to any of the mutations provided herein (e.g., mutations in ecTadA). One of skill in the art will be able to identify the corresponding residue in any homologous protein and in the respective encoding nucleic acid by methods well known in the art, e.g., by sequence alignment and determination of homologous residues. Accordingly, one of skill in the art would be able to generate mutations in any naturally- occurring adenosine deaminase (e.g., having homology to ecTadA) that corresponds to any of the mutations described herein, e.g., any of the mutations identified in ecTadA. In some embodiments, the adenosine deaminase is from a prokaryote. In some embodiments, the adenosine deaminase is from a bacterium. In some embodiments, the adenosine deaminase is from Escherichia coli, Staphylococcus aureus, Salmonella typhi, Shewanella putrefaciens, Haemophilus influenzae, Caulobacter crescentus, or Bacillus subtilis. In some embodiments, the adenosine deaminase is from E. coli.

[00279] In some embodiments, the adenosine deaminase comprises an amino acid sequence that is at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or at least 99.5% identical to any one of the amino acid sequences set forth in any one of SEQ ID NOs: 62-84, or to any of the adenosine deaminases provided herein. It should be appreciated that adenosine deaminases provided herein may include one or more mutations (e.g., any of the mutations provided herein). The disclosure provides adenosine deaminases with a certain percent identity plus any of the mutations or combinations thereof described herein. In some embodiments, the adenosine deaminase comprises an amino acid sequence that has 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 21, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, or more mutations compared to any one of the amino acid sequences set forth in SEQ ID NOs: 62-84, or any of the adenosine deaminases provided herein. In some embodiments, the adenosine deaminase comprises an amino acid sequence that has at least 5, at least 10, at least 15, at least 20, at least 25, at least 30, at least 35, at least 40, at least 45, at least 50, at least 60, at least 70, at least 80, at least 90, at least 100, at least 110, at least 120, at least 130, at least 140, at least 150, at least 160, or at least 170 identical contiguous amino acid residues as compared to any one of the amino acid sequences set forth in SEQ ID NOs: 62-84, or any of the adenosine deaminases provided herein.

[00280] In some embodiments, the adenosine deaminase comprises an E59X mutation in ecTadA SEQ ID NO: 64, or a corresponding mutation in another adenosine deaminase, where X indicates any amino acid other than the corresponding amino acid in the wild-type adenosine deaminase. In particular embodiments, the adenosine deaminase comprises a E59A mutation in SEQ ID NO: 64, or a corresponding mutation in another adenosine deaminase.

[00281] In some embodiments, the adenosine deaminase comprises a D108X mutation in ecTadA SEQ ID NO: 64, or a corresponding mutation in another adenosine deaminase, where X indicates any amino acid other than the corresponding amino acid in the wild-type adenosine deaminase. In some embodiments, the adenosine deaminase comprises a D108W, D108Q, D108F, D108K, or D108M mutation in SEQ ID NO: 64, or a corresponding mutation in another adenosine deaminase. In particular embodiments, the adenosine deaminase comprises a D108W mutation in SEQ ID NO: 64, or a corresponding mutation in another adenosine deaminase. It should be appreciated, however, that additional deaminases may similarly be aligned to identify homologous amino acid residues that may be mutated as provided herein.

[00282] In some embodiments, the adenosine deaminase comprises TadA 7.10, whose sequence is provided as SEQ ID NO: 65, or a variant thereof. TadA7.10 comprises the following mutations in ecTadA: W23R, H36L, P48A, R51L, L84F, A106V, D108N, H123Y, S146C, D147Y, R152P, E155V, I156F, K157N.

[00283] In particular embodiments, the adenosine deaminase comprises an N108W mutation in SEQ ID NO: 65, an embodiment also referred to as TadA 7.10(N108W). Its sequence is provided as SEQ ID NO: 67.

[00284] In some embodiments, the adenosine deaminase comprises an A106X mutation in ecTadA SEQ ID NO: 64, or a corresponding mutation in another adenosine deaminase, where X indicates any amino acid other than the corresponding amino acid in the wild-type adenosine deaminase. In some embodiments, the adenosine deaminase comprises an A106V mutation in SEQ ID NO: 64, or a corresponding mutation in another adenosine deaminase. In some embodiments, the adenosine deaminase comprises an A106Q, A106F, A106W, or A106M mutation in SEQ ID NO: 64, or a corresponding mutation in another adenosine deaminase.

[00285] In particular embodiments, the adenosine deaminase comprises a V106W mutation in SEQ ID NO: 65, an embodiment also referred to as TadA 7.10(V106W). Its sequence is provided as SEQ ID NO: 66.

[00286] In some embodiments, the adenosine deaminase comprises a R47X mutation in SEQ ID NO: 65, or a corresponding mutation in another adenosine deaminase, where the presence of X indicates any amino acid other than the corresponding amino acid in the wild-type adenosine deaminase. In some embodiments, the adenosine deaminase comprises a R47Q, R47F, R47W, or R47M mutation in SEQ ID NO: 65, or a corresponding mutation in another adenosine deaminase.

[00287] In particular embodiments, the adenosine deaminase comprises a R47Q, R47F, R47W, or R47M mutation in SEQ ID NO: 65.

[00288] In particular embodiments, the adenosine deaminase comprises a V106Q mutation and an N108W mutation in SEQ ID NO: 65. In particular embodiments, the adenosine deaminase comprises a V106W mutation, an N108W mutation and an R47Z mutation, wherein Z is selected from the residues consisting of Q, F, W and M, in SEQ ID NO: 65.

[00289] It should be appreciated that any of the mutations provided herein (e.g., based on the ecTadA amino acid sequence of SEQ ID NO: 64) may be introduced into other adenosine deaminases, such as S. aureus TadA (saTadA), or other adenosine deaminases (e.g., bacterial adenosine deaminases), such as those sequences provided below. It would be apparent to the skilled artisan how to identify amino acid residues from other adenosine deaminases that are homologous to the mutated residues in ecTadA. Thus, any of the mutations identified in ecTadA may be made in other adenosine deaminases that have homologous amino acid residues. It should also be appreciated that any of the mutations provided herein may be made individually or in any combination in ecTadA or another adenosine deaminase. For example, an adenosine deaminase may contain a D108N, an A106V, and/or a R47Q mutation in ecTadA SEQ ID NO: 64, or a corresponding mutation in another adenosine deaminase.

[00290] In some embodiments, the adenosine deaminase comprises one, two, or three mutations selected from the group consisting of D108, A106, and R47 in SEQ ID NO: 64, or a corresponding mutation or mutations in another adenosine deaminase.

[00291] In other aspects, the disclosure provides adenine base editors with broadened target sequence compatibility. In general, native ecTadA deaminates the adenine in the sequence UAC (e.g., the target sequence) of the anticodon loop of tRNA ^Arg . Without wishing to be bound by any particular theory, in order to expand the utility of ABEs comprising one or more ecTadA deaminases, such as

any of the adenosine deaminases provided herein, the adenosine deaminase proteins were optimized

to recognize a wide variety of target sequences within the protospacer sequence without

compromising the editing efficiency of the adenosine nucleobase editor complex. In some

embodiments, the target sequence is an A in the middle of a 5’-NAN-3’ sequence, wherein N is T, C,

G, or A. In some embodiments, the target sequence comprises 5’-TAC-3’. In some embodiments, the

target sequence comprises 5’-GAA-3’.

[00292] In some embodiments, the adenosine deaminase is an N-terminal truncated E. coli TadA. In

certain embodiments, the adenosine deaminase comprises the amino acid sequence:

[00293] In some embodiments, the TadA deaminase is a full-length E. coli TadA deaminase

(ecTadA). For example, in certain embodiments, the adenosine deaminase comprises the amino acid

sequence:

[00294] It should be appreciated, however, that additional adenosine deaminases useful in the

present application would be apparent to the skilled artisan and are within the scope of this disclosure.

For example, the adenosine deaminase may be a homolog of an ADAT. Exemplary ADAT homologs

include, without limitation:

[00295] Staphylococcus aureus TadA: [00296] Bacillus subtilis TadA:

[00316] Any two or more of the adenosine deaminases described herein may be connected to one another (e.g. by a linker) within an adenosine deaminase domain of the fusion proteins provided herein. For instance, the fusion proteins provided herein may contain only two adenosine deaminases. In some embodiments, the adenosine deaminases are the same. In some embodiments, the adenosine deaminases are any of the adenosine deaminases provided herein. In some embodiments, the adenosine deaminases are different. In some embodiments, the first adenosine deaminase is any of the adenosine deaminases provided herein, and the second adenosine is any of the adenosine deaminases provided herein, but is not identical to the first adenosine deaminase. In some embodiments, the fusion protein comprises two adenosine deaminases (e.g., a first adenosine deaminase and a second adenosine deaminase). In some embodiments, the fusion protein comprises a first adenosine deaminase and a second adenosine deaminase. In some embodiments, the first adenosine deaminase is N-terminal to the second adenosine deaminase in the fusion protein. In some embodiments, the first adenosine deaminase is C-terminal to the second adenosine deaminase in the fusion protein. In some embodiments, the first adenosine deaminase and the second deaminase are fused directly or via a linker.

[00317] In particular embodiments, the base editors disclosed herein comprise a heterodimer of a first adenosine deaminase that is N-terminal to a second adenosine deaminase, wherein the first adenosine deaminase comprises a sequence with at least 80%, 85%, 90%, 95%, 98%, 99%, or 99.5% sequence identity to SEQ ID NO: 62-84; and the second adenosine deaminase comprises a sequence with at least 80%, 85%, 90%, 95%, 98%, 99%, or 99.5% sequence identity to SEQ ID NO: 62-84.

[00318] In other embodiments, the second adenosine deaminase of the base editors provided herein comprises a sequence with at least 80%, 85%, 90%, 95%, 98%, 99%, or 99.5% sequence identity to SEQ ID NO: 65 (TadA 7.10), wherein any sequence variation may only occur in amino acid positions other than R47, V106 or N108 of SEQ ID NO: 65. In other words, these embodiments must contain amino acid substitutions at R47, V106 or N108 of SEQ ID NO: 65.

[00319] In other embodiments, the second adenosine deaminase of the heterodimer comprises a sequence with at least 80%, 85%, 90%, 95%, 98%, 99%, or 99.5% sequence identity to SEQ ID NO: 62-84.

Base editor constructs

[00320] Any of the Cas9 domains (e.g., Cas9 domains that recognize a non-canonical PAM sequence) disclosed herein may be fused to a second protein, thus providing fusion proteins that comprise a Cas9 domain as provided herein and a second protein, or a“fusion partner.” In some embodiments, the second protein is an effector domain. As used herein, an“effector domain” refers to a molecule (e.g., a protein) that regulates a biological activity and/or is capable of modifying a biological molecule (e.g., a protein, or a nucleic acid such as DNA or RNA). In some embodiments, the effector domain is a protein. In some embodiments, the effector domain is capable of modifying a protein (e.g., a histone). In some embodiments, the effector domain is capable of modifying DNA (e.g., genomic DNA). In some embodiments the effector domain is capable of modifying RNA (e.g., mRNA). In some embodiments, the effector molecule is a nucleic acid editing domain. In some embodiments, the effector molecule is capable of regulating an activity of a nucleic acid (e.g., transcription, and/or translation). Exemplary effector domains include, without limitation, a deaminase, a nuclease, a nickase, a recombinase, a methyltransferase, a methylase, an acetylase, an acetyltransferase, a transcriptional activator, or a transcriptional repressor domain. In some embodiments, the effector domain is a nucleic acid editing domain. Some aspects of the disclosure provide fusion proteins comprising a Cas9 domain and a nucleic acid editing domain.

[00321] In some embodiments, the fusion proteins provided herein exhibit increased activity on a target sequence that does not comprise the canonical PAM (5¢-NGG-3¢) at its 3ʹ end as compared to a fusion protein comprising Streptococcus pyogenes Cas9 as provided by SEQ ID NO: 2. In some embodiments, the fusion protein exhibits an activity on a target sequence having a 3ʹ end that is not directly adjacent to the canonical PAM sequence (5¢-NGG-3¢) that is at least 2-fold, at least 3-fold, at least 4-fold, at least 5-fold, at least 10-fold, at least 50-fold, at least 100-fold, at least 500-fold, at least 1,000-fold, at least 5,000-fold, at least 10,000-fold, at least 50,000-fold, at least 100,000-fold, at least 500,000-fold, or at least 1,000,000-fold increased as compared to the activity of a fusion protein comprising Streptococcus pyogenes Cas9 as provided by SEQ ID NO: 2 on the same target sequence. In some embodiments, the 3ʹ end of the target sequence is directly adjacent to a sequence selected from the group consisting of NGT, NGA, NGC, and NNG, wherein N is an A, G, T, or C. In some embodiments, the 3ʹ end of the target sequence is directly adjacent to a sequence selected from the group consisting of CGG, AGT, TGG, AGT, CGT, GGG, CGT, TGT, GGT, AGC, CGC, TGC, GGC, AGA, CGA, TGA, GGA, GAA, GAT, and CAA. In some embodiments, the fusion protein activity is measured by a nuclease assay, a deamination assay, a transcriptional activation assay, a binding assay, PCR, or sequencing. In some embodiments, the transcriptional activation assay is a GFP activation assay. In some embodiments, sequencing is used to measure indel formation. In some embodiments, the increased activity is increased binding. In some embodiments, the increased activity is increased deamination of a nucleobase in the target sequence.

[00322] Some aspects of the disclosure provide a fusion protein comprising a Cas9 domain fused to a nucleic acid editing domain, wherein the nucleic acid editing domain is fused to the N-terminus of the Cas9 domain. In some embodiments, the nucleic acid editing domain is fused to the C-terminus of the Cas9 domain. In some embodiments, the Cas9 domain and the nucleic acid editing-editing domain are fused via a linker. In some embodiments, the linker comprises a (GGGS)n (SEQ ID NO: 93), a (GGGGS)n (SEQ ID NO: 95), a (G)n (SEQ ID NO: 97), an (EAAAK)n (SEQ ID NO: 99), a (GGS)n (SEQ ID NO: 101), (SGGS) _n (SEQ ID NO: 91), an SGSETPGTSESATPES (SEQ ID NO: 89) motif (see, e.g., Guilinger JP, Thompson DB, Liu DR. Fusion of catalytically inactive Cas9 to FokI nuclease improves the specificity of genome modification. Nat. Biotechnol.2014; 32(6): 577-82; the entire contents are incorporated herein by reference), or a combination of any of these, wherein n is independently an integer between 1 and 30. In some embodiments, n is independently 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30, or, if more than one linker or more than one linker motif is present, any combination thereof. In some embodiments, the linker comprises a (GGS)n motif (SEQ ID NO: 101), wherein n is 1,2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or 15. Additional suitable linker motifs and linker configurations will be apparent to those of ordinary skill in the art (e.g., SEQ ID NOs: 89-112). In some embodiments, suitable linker motifs and configurations include those described in Chen et al., Fusion protein linkers: property, design and functionality. Adv. Drug Deliv. Rev.2013; 65(10):1357-69, the entire contents of which are incorporated herein by reference. Additional suitable linker sequences will be apparent to those of ordinary skill in the art based on the instant disclosure. In some embodiments, the general architecture of exemplary Cas9 fusion proteins provided herein comprises the structure: [NH ₂ ]-[nucleic acid editing domain]-[Cas9 domain]-[COOH];

[NH ₂ ]-[nucleic acid editing domain]-[linker]-[Cas9 domain]-[COOH]; [NH2]-[Cas9 domain]-[nucleic acid editing domain]-[COOH]; or

[NH2]-[Cas9 domain]-[linker]-[nucleic acid editing domain]-[COOH],

wherein NH ₂ is the N-terminus of the fusion protein, and COOH is the C-terminus of the fusion protein. In some embodiments, the“]-[“ used in the general architecture above indicates the presence of an optional linker sequence.

[00323] The fusion proteins of the present disclosure may comprise one or more additional features. For example, in some embodiments, the fusion protein comprises a nuclear localization sequence (NLS). In some embodiments, the NLS of the fusion protein is localized between the nucleic acid editing domain and the Cas9 domain. In some embodiments, the NLS of the fusion protein is localized C-terminal to the Cas9 domain. In some embodiments, the NLS of the fusion protein is localized N-terminal to the Cas9 domain. In some embodiments, the NLS comprises the amino acid sequence of SEQ ID NO: 113 or 114. In some embodiments, the NLS comprises the amino acid sequence of SEQ ID NO: 113.

[00324] Other exemplary features that may be present are localization sequences, such as cytoplasmic localization sequences, export sequences, such as nuclear export sequences, or other localization sequences, as well as sequence tags that are useful for solubilization, purification, or detection of the fusion proteins. Suitable protein tags provided herein include, but are not limited to, biotin carboxylase carrier protein (BCCP) tags, myc-tags, calmodulin-tags, FLAG-tags,

hemagglutinin (HA)-tags, polyhistidine tags, also referred to as histidine tags or His-tags, maltose binding protein (MBP)-tags, nus-tags, glutathione-S-transferase (GST)-tags, green fluorescent protein (GFP)-tags, thioredoxin-tags, S-tags, Softags (e.g., Softag 1, Softag 3), strep-tags , biotin ligase tags, FlAsH tags, V5 tags, and SBP-tags. Additional suitable sequences will be apparent to those of ordinary skill in the art. In some embodiments, the fusion protein comprises one or more His tags.

[00325] In some embodiments, the nucleic acid editing domain is a deaminase. In some

embodiments, the deaminase is a cytidine deaminase. For example, in some embodiments, the general architecture of exemplary Cas9 fusion proteins with a cytidine deaminase domain comprises the structure:

[NH ₂ ]-[NLS]-[cytidine deaminase]-[Cas9]-[COOH];

[NH ₂ ]-[Cas9]-[cytidine deaminase]-[COOH];

[NH ₂ ]-[cytidine deaminase]-[Cas9]-[COOH]; or

[NH ₂ ]-[cytidine deaminase]-[Cas9]-[NLS]-[COOH],

wherein NLS is a nuclear localization sequence, NH ₂ is the N-terminus of the fusion protein, and COOH is the C-terminus of the fusion protein. Nuclear localization sequences are known in the art and would be apparent to the skilled artisan. For example, NLS sequences are described in Plank et al., International PCT Application, PCT/EP2000/011690, the contents of which are incorporated herein by reference for their disclosure of exemplary nuclear localization sequences. In some embodiments, a NLS comprises the amino acid sequence PKKKRKV (SEQ ID NO: 113) or

MDSLLMNRRKFLYQFKNVRWAKGRRETYLC (SEQ ID NO: 114). In some embodiments, a linker is inserted between the Cas9 and the cytidine deaminase. In some embodiments, the NLS is located C- terminal of the Cas9 domain. In some embodiments, the NLS is located N-terminal of the Cas9 domain. In some embodiments, the NLS is located between the cytidine deaminase and the Cas9 domain. In some embodiments, the NLS is located N-terminal of the cytidine deaminase domain. In some embodiments, the NLS is located C-terminal of the cytidine deaminase domain. In some embodiments, the“]-[“ used in the general architecture above indicates the presence of an optional linker sequence.

[00326] In some embodiments, the fusion protein comprises any one of nucleic acid editing domains provided herein. In some embodiments, the nucleic acid editing domain is a cytidine or adenosine deaminase domain provided herein.

[00327] In some embodiments, the cytidine deaminase domain and the Cas9 domain are fused to each other via a linker. Various linker lengths and flexibilities between the deaminase domain (e.g., AID, APOBEC family deaminase) and the Cas9 domain can be employed, for example, ranging from very flexible linkers of the form (GGGS)n (SEQ ID NO: 93), (GGGGS)n (SEQ ID NO: 95), (GGS)n (SEQ ID NO: 101), and (G)n (SEQ ID NO: 97), to more rigid linkers of the form (EAAAK)n (SEQ ID NO: 99), (SGGS)n (SEQ ID NO: 91), SGGS(GGS)n (SEQ ID NO: 103), SGSETPGTSESATPES (SEQ ID NO: 89) (see, e.g., Guilinger JP, Thompson DB, Liu DR. Fusion of catalytically inactive Cas9 to FokI nuclease improves the specificity of genome modification. Nat. Biotechnol.2014; 32(6): 577-82; the entire contents are incorporated herein by reference),

(SGGS)n-SGSETPGTSESATPES-(SGGS)n (SEQ ID NO: 98), and (XP)n, wherein n is an integer between 1 and 30, inclusive, in order to achieve the optimal length for deaminase activity for the specific application. In some embodiments, the linker comprises a (GGS)n motif, wherein n is 1, 3, or 7. In some embodiments, the linker comprises a SGSETPGTSESATPES (SEQ ID NO: 89) motif. In some embodiments, the linker comprises a (SGGS)2-SGSETPGTSESATPES-(SGGS)2 (SEQ ID NO: 96) motif.

[00328] In some embodiments, the fusion protein comprises a Cas9 domain (e.g., a Cas9 domain comprising one or more mutations that recognizes a non-canonical PAM sequence) fused to a cytidine deaminase domain, wherein the fusion protein comprises the amino acid sequence of SEQ ID NO: 2. In some embodiments, the fusion protein comprises any one of the amino acid sequences of SEQ ID NOs: 122-132.

[00329] Some aspects of the disclosure relate to fusion proteins that comprise a uracil glycosylase inhibitor (UGI) domain. In some embodiments, any of the fusion proteins provided herein that comprise a Cas9 domain (e.g., a Cas9 domain comprising one or more mutations that recognizes a non-canonical PAM sequence) may be further fused to a UGI domain either directly or via a linker. Some aspects of this disclosure provide deaminase-dCas9 fusion proteins, deaminase-nuclease active Cas9 fusion proteins and deaminase-Cas9 nickase fusion proteins with increased nucleobase editing efficiency. Without wishing to be bound by any particular theory, cellular DNA-repair response to the presence of U:G heteroduplex DNA may be responsible for the decrease in nucleobase editing efficiency in cells. For example, uracil DNA glycosylase (UDG) catalyzes removal of U from DNA in cells, which may initiate base excision repair, with reversion of the U:G pair to a C:G pair as the most common outcome. A Uracil DNA Glycosylase Inhibitor (UGI) may inhibit human UDG activity. Thus, this disclosure contemplates a fusion protein comprising a Cas9 domain and a nucleic acid editing domain (e.g., a deaminase) further fused to a UGI domain. In some embodiments, the fusion protein comprising a Cas9 nickase-nucleic acid editing domain further fused to a UGI domain. In some embodiments, the fusion protein comprising a dCas9-nucleic acid editing domain further fused to a UGI domain. It should be understood that the use of a UGI domain may increase the editing efficiency of a nucleic acid editing domain that is capable of catalyzing, for example, a C to U change. For example, fusion proteins comprising a UGI domain may be more efficient in deaminating C residues.

[00330] In some embodiments, the fusion protein comprises the structure:

[nucleic acid editing domain]-[optional linker sequence]-[Cas9]-[optional linker sequence]- [UGI];

[nucleic acid editing domain]-[optional linker sequence]-[UGI]-[optional linker sequence]- [Cas9];

[UGI]-[optional linker sequence]-[ nucleic acid editing domain]-[optional linker sequence]- [Cas9];

[UGI]-[optional linker sequence]-[Cas9]-[optional linker sequence]-[ nucleic acid editing domain];

[Cas9]-[optional linker sequence]-[ nucleic acid editing domain]-[optional linker sequence]- [UGI]; or

[Cas9]-[optional linker sequence]-[UGI]-[optional linker sequence]-[ nucleic acid editing domain].

[00331] In some embodiments, the fusion protein comprises the structure: [deaminase]-[optional linker sequence]-[Cas9]-[optional linker sequence]-[UGI];

[deaminase]-[optional linker sequence]-[UGI]-[optional linker sequence]-[Cas9];

[UGI]-[optional linker sequence]-[deaminase]-[optional linker sequence]-[Cas9];

[UGI]-[optional linker sequence]-[Cas9]-[optional linker sequence]-[deaminase];

[Cas9]-[optional linker sequence]-[deaminase]-[optional linker sequence]-[UGI]; or

[Cas9]-[optional linker sequence]-[UGI]-[optional linker sequence]-[deaminase].

[00332] In some embodiments, the fusion protein comprises the structure:

[cytidine deaminase]-[optional linker sequence]-[Cas9]-[optional linker sequence]-[UGI]; [cytidine deaminase]-[optional linker sequence]-[UGI]-[optional linker sequence]-[Cas9]; [UGI]-[optional linker sequence]-[cytidine deaminase]-[optional linker sequence]-[Cas9]; [UGI]-[optional linker sequence]-[Cas9]-[optional linker sequence]-[cytidine deaminase]; [Cas9]-[optional linker sequence]-[cytidine deaminase]-[optional linker sequence]-[UGI]; or [Cas9]-[optional linker sequence]-[UGI]-[optional linker sequence]-[cytidine deaminase].

[00333] In some embodiments, the fusion proteins provided herein do not comprise a linker sequence. In some embodiments, one or both of the optional linker sequences are present.

[00334] In some embodiments, the“-” used in the general architecture above indicates the presence of an optional linker sequence. In some embodiments, the fusion proteins comprising a UGI domain further comprise a nuclear targeting sequence, for example, a nuclear localization sequence. In some embodiments, fusion proteins provided herein further comprise a nuclear localization sequence (NLS). In some embodiments, the NLS is fused to the N-terminus of the fusion protein. In some embodiments, the NLS is fused to the C-terminus of the fusion protein. In some embodiments, the NLS is fused to the N-terminus of the UGI protein. In some embodiments, the NLS is fused to the C-terminus of the UGI protein. In some embodiments, the NLS is fused to the N-terminus of the Cas9 domain. In some embodiments, the NLS is fused to the C-terminus of the Cas9 domain. In some embodiments, the NLS is fused to the N-terminus of the deaminase. In some embodiments, the NLS is fused to the C-terminus of the deaminase. In some embodiments, the NLS is fused to the N-terminus of the second Cas9. In some embodiments, the NLS is fused to the C-terminus of the second Cas9. In some embodiments, the NLS is fused to the fusion protein via one or more linkers. In some embodiments, the NLS is fused to the fusion protein without a linker. In some embodiments, the NLS comprises an amino acid sequence of any one of the NLS sequences provided or referenced herein. In some embodiments, the NLS comprises an amino acid sequence as set forth in SEQ ID NO: 113 or SEQ ID NO: 114.

[00335] In some embodiments, a UGI domain comprises a wild-type UGI or a UGI as set forth in any of SEQ ID NOs: 115-120. In some embodiments, the UGI proteins provided herein include fragments of UGI and proteins homologous to a UGI or a UGI fragment. For example, in some embodiments, a UGI domain comprises a fragment of the amino acid sequence set forth in SEQ ID NO: 115. In some embodiments, a UGI fragment comprises an amino acid sequence that comprises at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or at least 99.5% of the amino acid sequence as set forth in SEQ ID NO: 115. In some embodiments, a UGI comprises an amino acid sequence homologous to the amino acid sequence set forth in SEQ ID NO: 115 or an amino acid sequence homologous to a fragment of the amino acid sequence set forth in SEQ ID NO: 115. In some embodiments, proteins comprising UGI or fragments of UGI or homologs of UGI or UGI fragments are referred to as“UGI variants.” A UGI variant shares homology to UGI, or a fragment thereof. For example a UGI variant is at least 70% identical, at least 75% identical, at least 80% identical, at least 85% identical, at least 90% identical, at least 95% identical, at least 96% identical, at least 97% identical, at least 98% identical, at least 99% identical, at least 99.5% identical, or at least 99.9% identical to a wild type UGI or a UGI as set forth in SEQ ID NO: 115. In some embodiments, the UGI variant comprises a fragment of UGI, such that the fragment is at least 70% identical, at least 80% identical, at least 90% identical, at least 95% identical, at least 96% identical, at least 97% identical, at least 98% identical, at least 99% identical, at least 99.5% identical, or at least 99.9% to the corresponding fragment of wild-type UGI or a UGI as set forth in SEQ ID NO: 115.

[00336] Suitable UGI protein and nucleotide sequences are provided herein and additional suitable UGI sequences are known to those in the art, and include, for example, those published in Wang et al., Uracil-DNA glycosylase inhibitor gene of bacteriophage PBS2 encodes a binding protein specific for uracil-DNA glycosylase. J. Biol. Chem.264:1163-1171(1989); Lundquist et al., Site- directed mutagenesis and characterization of uracil-DNA glycosylase inhibitor protein. Role of specific carboxylic amino acids in complex formation with Escherichia coli uracil-DNA glycosylase. J. Biol. Chem.272:21408-21419(1997); Ravishankar et al., X-ray analysis of a complex of

Escherichia coli uracil DNA glycosylase (EcUDG) with a proteinaceous inhibitor. The structure elucidation of a prokaryotic UDG. Nucleic Acids Res.26:4880-4887(1998); and Putnam et al., Protein mimicry of DNA from crystal structures of the uracil-DNA glycosylase inhibitor protein and its complex with Escherichia coli uracil-DNA glycosylase. J. Mol. Biol.287:331-346(1999), the entire contents of each of which are incorporated herein by reference.

[00337] It should be appreciated that additional proteins may be uracil glycosylase inhibitors. For example, other proteins that are capable of inhibiting (e.g., sterically blocking) a uracil- DNA glycosylase base-excision repair enzyme are within the scope of this disclosure. Additionally, any proteins that block or inhibit base-excision repair as also within the scope of this disclosure. In some embodiments, a protein that binds DNA is used. In another embodiment, a substitute for UGI is used. In some embodiments, a uracil glycosylase inhibitor is a protein that binds single-stranded DNA. For example, a uracil glycosylase inhibitor may be a Erwinia tasmaniensis single-stranded binding protein. In some embodiments, the single-stranded binding protein comprises the amino acid sequence (SEQ ID NO: 118). In some embodiments, a uracil glycosylase inhibitor is a protein that binds uracil. In some embodiments, a uracil glycosylase inhibitor is a protein that binds uracil in DNA. In some embodiments, a uracil glycosylase inhibitor is a catalytically inactive uracil DNA- glycosylase protein. In some embodiments, a uracil glycosylase inhibitor is a catalytically inactive uracil DNA-glycosylase protein that does not excise uracil from the DNA. For example, a uracil glycosylase inhibitor is a UdgX. In some embodiments, the UdgX comprises the amino acid sequence (SEQ ID NO: 119). As another example, a uracil glycosylase inhibitor is a catalytically inactive UDG. In some embodiments, a catalytically inactive UDG comprises the amino acid sequence (SEQ ID NO: 55). It should be appreciated that other uracil glycosylase inhibitors would be apparent to the skilled artisan and are within the scope of this disclosure. In some embodiments, a uracil glycosylase inhibitor is a protein that is homologous to any one of SEQ ID NOs: 115-120. In some embodiments, a uracil glycosylase inhibitor is a protein that is at least 50% identical, at least 55% identical, at least 60% identical, at least 65% identical, at least 70% identical, at least 75% identical, at least 80% identical at least 85% identical, at least 90% identical, at least 95% identical, at least 96% identical, at least 98% identical, at least 99% identical, or at least 99.5% identical to any one of SEQ ID NOs: 115- 120.

[00341] In various embodiments, the fusion protein is:

[00342] xCas9(3.7)–BE3 (APOBEC–linker(16aa)–xCas9(3.7)n–linker(4aa)–UGI–l inker(4aa)– [00345] In some embodiments, any of the fusion proteins provided herein comprise a second UGI domain. In some embodiments, the second UGI domain comprises a wild-type UGI or a UGI as set forth in SEQ ID NO: 115-120. In some embodiments, the UGI proteins provided herein include fragments of UGI and proteins homologous to a UGI or a UGI fragment. For example, in some embodiments, the second UGI domain comprises a fragment of the amino acid sequence set forth in SEQ ID NO: 115. In some embodiments, a UGI fragment comprises an amino acid sequence that comprises at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or at least 99.5% of the amino acid sequence as set forth in SEQ ID NO: 115. In some embodiments, the second UGI domain comprises an amino acid sequence homologous to the amino acid sequence set forth in SEQ ID NO: 115 or an amino acid sequence homologous to a fragment of the amino acid sequence set forth in SEQ ID NO: 115. In some embodiments, proteins comprising UGI or fragments of UGI or homologs of UGI or UGI fragments are referred to as“UGI variants.” A UGI variant shares homology to UGI, or a fragment thereof. For example a UGI variant is at least 70% identical, at least 75% identical, at least 80% identical, at least 85% identical, at least 90% identical, at least 95% identical, at least 96% identical, at least 97% identical, at least 98% identical, at least 99% identical, at least 99.5% identical, or at least 99.9% identical to a wild type UGI or a UGI as set forth in SEQ ID NO: 39. In some embodiments, the UGI variant comprises a fragment of UGI, such that the fragment is at least 70% identical, at least 80% identical, at least 90% identical, at least 95% identical, at least 96% identical, at least 97% identical, at least 98% identical, at least 99% identical, at least 99.5% identical, or at least 99.9% to the corresponding fragment of wild-type UGI or a UGI as set forth in SEQ ID NO: 115.

[00346] In some embodiments, the fusion protein comprises the amino acid sequence of any one of SEQ ID NOs: 122-132. In some embodiments, the fusion protein comprises the amino acid sequence of SEQ ID NO: 122. In some embodiments, the fusion protein consists of the amino acid sequence of SEQ ID NO: 123. In some embodiments, the fusion protein comprises the amino acid sequence of SEQ ID NO: 124. In some embodiments, the fusion protein consists of the amino acid sequence of SEQ ID NO: 125. In some embodiments, the fusion protein comprises the amino acid sequence of SEQ ID NO: 126. In some embodiments, the fusion protein consists of the amino acid sequence of SEQ ID NO: 127. In some embodiments, the fusion protein comprises an amino acid sequence that is at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or at least 99.5% identical to the amino acid sequence as set forth in SEQ ID NOs: 56-61. In some embodiments, the Cas9 domain is replaced with any of the Cas9 domains comprising one or more mutations provided herein.

[00347] xCas93.6-BE4 (APOBEC1-linker(32aa)-xCas9(3.6)n-linker(9aa)-UGI-linker(9aa )-UGI):

[00350] In some embodiments, any of the fusion proteins provided herein may further comprise a Gam protein. The term“Gam protein,” as used herein, refers generally to proteins capable of binding to one or more ends of a double strand break of a double stranded nucleic acid (e.g., double stranded DNA). In some embodiments, the Gam protein prevents or inhibits degradation of one or more strands of a nucleic acid at the site of the double strand break. In some embodiments, a Gam protein is a naturally-occurring Gam protein from bacteriophage Mu, or a non-naturally occurring variant thereof. Fusion proteins comprising Gam proteins are described in Komor et al. (2017) Improved Base Excision Repair Inhibition and Bateriophage Mu Gam Protein Yields C:G-to-T:A base editors with higher efficiency and product purity. Sci Adv, 3: eaao4774; the entire contents of which is incorporated by reference herein. In some embodiments, the Gam protein comprises an amino acid sequence that is at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 92%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or at least 99.5% identical to the amino acid sequence provided by SEQ ID NO: 121. In some embodiments, the Gam protein comprises the amino acid sequence of SEQ ID NO: 121. In some embodiments, the fusion protein (e.g., BE4-Gam of SEQ ID NO: 126) comprises a Gam protein, wherein the Cas9 domain of BE4 is replaced with any of the Cas9 domains provided herein.

[00351] Gam from bacteriophage Mu:

AKPAKRIKSAAAAYVPQNRDAVITDIKRIGDLQREASRLETEMNDAIAEITEKFAARIAP IKTDIETL SKGVQGWCEANRDELTNGGKVKTANLVTGDVSWRVRPPSVSIRGMDAVMETLERLGLQRF IRTKQEIN KEAILLEPKAVAGVAGITVKSGIEDFSIIPFEQEAGI (SEQ ID NO: 121)

[00352] BE4-Gam:

[00353] Some aspects of the disclosure provide fusion proteins comprising a nucleic acid Cas9 domain (e.g., ) and an adenosine deaminase. In some embodiments, any of the fusion proteins provided herein are base editors. Some aspects of the disclosure provide fusion proteins comprising a Cas9 domain and an adenosine deaminase. The Cas9 domain may be any of the Cas9 domains (e.g., a Cas9 domain) provided herein. In some embodiments, any of the Cas9 domains (e.g., a Cas9 domain) provided herein may be fused with any of the adenosine deaminases provided herein. In some embodiments, the fusion protein comprises the structure:

[NH ₂ ]-[adenosine deaminase]-[Cas9]-[COOH]; or

[NH ₂ ]-[Cas9]-[adenosine deaminase]-[COOH].

[00354] In some embodiments, the fusion proteins comprising an adenosine deaminase and a Cas9 domain do not include a linker sequence. In some embodiments, a linker is present between the adenosine deaminase domain and the Cas9 domain. In some embodiments, the“-“ used in the general architecture above indicates the presence of an optional linker. In some embodiments, the adenosine deaminase and the Cas9 domain are fused via any of the linkers provided herein. For example, in some embodiments the adenosine deaminase and the Cas9 domain are fused via any of the linkers provided below. In some embodiments, the linker comprises the amino acid sequence of any one of SEQ ID NOs: 89-112. In some embodiments, the adenosine deaminase and the Cas9 domain are fused via a linker that comprises between 1 and 200 amino acids. In some embodiments, the adenosine deaminase and the Cas9 domain are fused via a linker that comprises from 1 to 5, 1 to 10, 1 to 20, 1 to 30, 1 to 40, 1 to 50, 1 to 60, 1 to 80, 1 to 100, 1 to 150, 1 to 200, 5 to 10, 5 to 20, 5 to 30, 5 to 40, 5 to 60, 5 to 80, 5 to 100, 5 to 150, 5 to 200, 10 to 20, 10 to 30, 10 to 40, 10 to 50, 10 to 60, 10 to 80, 10 to 100, 10 to 150, 10 to 200, 20 to 30, 20 to 40, 20 to 50, 20 to 60, 20 to 80, 20 to 100, 20 to 150, 20 to 200, 30 to 40, 30 to 50, 30 to 60, 30 to 80, 30 to 100, 30 to 150, 30 to 200, 40 to 50, 40 to 60, 40 to 80, 40 to 100, 40 to 150, 40 to 200, 50 to 6050 to 80, 50 to 100, 50 to 150, 50 to 200, 60 to 80, 60 to 100, 60 to 150, 60 to 200, 80 to 100, 80 to 150, 80 to 200, 100 to 150, 100 to 200, or 150 to 200 amino acids in length. In some embodiments, the adenosine deaminase and the Cas9 domain are fused via a linker that comprises 3, 4, 16, 24, 32, 64, 100, or 104 amino acids in length. In some embodiments, the adenosine deaminase and the Cas9 domain are fused via a linker that comprises the amino acid sequence SGSETPGTSESATPES (SEQ ID NO: 89),

SGGSSGGSSGSETPGTSESATPESSGGSSGGS (SEQ ID NO: 106), or

GGSGGSPGSPAGSPTSTEEGTSESATPESGPGTSTEPSEGSAPGSPAGSPTSTEEGT STEPSEGSAP GTSTEPSEGSAPGTSESATPESGPGSEPATSGGSGGS (SEQ ID NO: 110). In some embodiments, the adenosine deaminase and the Cas9 domain are fused via a linker comprising the amino acid sequence SGSETPGTSESATPES (SEQ ID NO: 89), which may also be referred to as the XTEN linker. In some embodiments, the linker is 24 amino acids in length. In some embodiments, the linker comprises the amino acid sequence SGGSSGGSSGSETPGTSESATPES (SEQ ID NO: 111). In some embodiments, the linker is 32 amino acids in length. In some embodiments, the linker comprises the amino acid sequence (SGGS)2-SGSETPGTSESATPES-(SGGS)2 (SEQ ID NO: 96), which may also be referred to as (SGGS)2-XTEN-(SGGS)2. In some embodiments, the linker comprises the amino acid sequence (SGGS)n-SGSETPGTSESATPES-(SGGS)n (SEQ ID NO: 98), wherein n is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10. In some embodiments, the linker is 40 amino acids in length. In some embodiments, the linker comprises the amino acid sequence

SGGSSGGSSGSETPGTSESATPESSGGSSGGSSGGSSGGS (SEQ ID NO: 106). In some embodiments, the linker is 64 amino acids in length. In some embodiments, the linker comprises the amino acid sequence

SGGSSGGSSGSETPGTSESATPESSGGSSGGSSGGSSGGSSGSETPGTSESATPESS GGSSGGS

(SEQ ID NO: 107). In some embodiments, the linker is 92 amino acids in length. In some embodiments, the linker comprises the amino acid sequence

PGSPAGSPTSTEEGTSESATPESGPGTSTEPSEGSAPGSPAGSPTSTEEGTSTEPSE GSAPGTSTEP SEGSAPGTSESATPESGPGSEPATS (SEQ ID NO: 108).

[00355] In some embodiments, the fusion proteins comprise one or more adenosine deaminases defined herein, or to any amino acid sequence that is at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or at least 99.5% identical to any one of the amino acid sequences set forth herein.

[00356] In some embodiments, the fusion proteins comprising an adenosine deaminase provided herein further comprise one or more nuclear targeting sequences, for example, a nuclear localization sequence (NLS). In some embodiments, a NLS comprises an amino acid sequence that facilitates the importation of a protein, that comprises an NLS, into the cell nucleus (e.g., by nuclear transport). In some embodiments, any of the fusion proteins provided herein further comprise a nuclear localization sequence (NLS). In some embodiments, the NLS is fused to the N-terminus of the fusion protein. In some embodiments, the NLS is fused to the C-terminus of the fusion protein. In some embodiments, the NLS is fused to the N-terminus of the IBR (e.g., dISN). In some

embodiments, the NLS is fused to the C-terminus of the IBR (e.g., dISN). In some embodiments, the NLS is fused to the N-terminus of the Cas9 domain. In some embodiments, the NLS is fused to the C- terminus of the Cas9 domain. In some embodiments, the NLS is fused to the N-terminus of the adenosine deaminase. In some embodiments, the NLS is fused to the C-terminus of the adenosine deaminase. In some embodiments, the NLS is fused to the fusion protein via one or more linkers. In some embodiments, the NLS is fused to the fusion protein without a linker. In some embodiments, the NLS comprises an amino acid sequence of any one of the NLS sequences provided or referenced herein. In some embodiments, the NLS comprises an amino acid sequence as set forth in SEQ ID NO: 37 or SEQ ID NO: 38. Additional nuclear localization sequences are known in the art and would be apparent to the skilled artisan. For example, NLS sequences are described in Plank et al.,

PCT/EP2000/011690, the contents of which are incorporated herein by reference for their disclosure of exemplary nuclear localization sequences. In some embodiments, a NLS comprises the amino acid sequence PKKKRKV (SEQ ID NO: 113). In some embodiments, a NLS comprises the amino acid sequence MDSLLMNRRKFLYQFKNVRWAKGRRETYLC (SEQ ID NO: 114).

[00357] In some embodiments, the general architecture of exemplary fusion proteins with an adenosine deaminase and a Cas9 domain comprises any one of the following structures, where NLS is a nuclear localization sequence (e.g., any NLS provided herein), NH ₂ is the N-terminus of the fusion protein, and COOH is the C-terminus of the fusion protein. Fusion proteins comprising an adenosine deaminase, a napDNAbp, and a NLS:

NH ₂ -[NLS]-[adenosine deaminase]-[Cas9]-COOH;

NH ₂ -[adenosine deaminase]-[NLS]-[Cas9]-COOH;

NH ₂ -[adenosine deaminase]-[Cas9]-[NLS]-COOH;

NH ₂ -[NLS]-[Cas9]-[adenosine deaminase]-COOH;

NH ₂ -[Cas9]-[NLS]-[adenosine deaminase]-COOH; and

NH ₂ -[Cas9]-[adenosine deaminase]-[NLS]-COOH.

[00358] In some embodiments, the fusion proteins comprising an adenosine deaminase domain provided herein do not comprise a linker. In some embodiments, a linker is present between one or more of the domains or proteins (e.g., adenosine deaminase, Cas9 domain, and/or NLS). In some embodiments, the“ -” used in the general architecture above indicates the presence of an optional linker. [00359] Some aspects of the disclosure provide fusion proteins that comprise a Cas9 domain (e.g. a Cas9 domain) and at least two adenosine deaminase domains. Without wishing to be bound by any particular theory, dimerization of adenosine deaminases (e.g., in cis or in trans) may improve the ability (e.g., efficiency) of the fusion protein to modify a nucleic acid base, for example to deaminate adenine. In some embodiments, any of the fusion proteins may comprise 2, 3, 4 or 5 adenosine deaminase domains. In some embodiments, any of the fusion proteins provided herein comprise two adenosine deaminases. In some embodiments, any of the fusion proteins provided herein contain only two adenosine deaminases. In some embodiments, the adenosine deaminases are the same. In some embodiments, the adenosine deaminases are any of the adenosine deaminases provided herein. In some embodiments, the adenosine deaminases are different. In some

embodiments, the first adenosine deaminase is any of the adenosine deaminases provided herein, and the second adenosine is any of the adenosine deaminases provided herein, but is not identical to the first adenosine deaminase. Additional fusion protein constructs comprising two adenosine deaminase domains suitable for use herein are illustrated in Gaudelli et al. (2017) Programmable base editing of A•T to G•C in genomic DNA without DNA cleavage, Nature, 551(23); 464-471; the entire contents of which is incorporated herein by reference.

[00360] In some embodiments, the first adenosine deaminase and the second deaminase are fused directly or via a linker. In some embodiments, the linker is any of the linkers provided herein. In some embodiments, the linker comprises the amino acid sequence of any one of the linker sequences disclosed herein (e.g., linkers of SEQ ID NOs: 21-36, 64, 65, 66, or 67). In some embodiments, the first adenosine deaminase is the same as the second adenosine deaminase. In some embodiments, the first adenosine deaminase and the second adenosine deaminase are any of the adenosine deaminases described herein. In some embodiments, the first adenosine deaminase and the second adenosine deaminase are different. In some embodiments, the first adenosine deaminase is any of the adenosine deaminases provided herein. In some embodiments, the second adenosine deaminase is any of the adenosine deaminases provided herein but is not identical to the first adenosine deaminase. In some embodiments, the first adenosine deaminase is an ecTadA adenosine deaminase. In some

embodiments, the first adenosine deaminase comprises an amino acid sequence that is at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or at least 99.5% identical to any one of the amino acid sequences set forth herein.

[00361] In some embodiments, the general architecture of exemplary fusion proteins with a first adenosine deaminase, a second adenosine deaminase, and a Cas9 domain (e.g. ) comprises any one of the following structures, where NLS is a nuclear localization sequence (e.g., any NLS provided herein), NH ₂ is the N-terminus of the fusion protein, and COOH is the C-terminus of the fusion protein:

NH ₂ -[first adenosine deaminase]-[second adenosine deaminase]-[Cas9]-COOH;

NH ₂ -[first adenosine deaminase]-[Cas9]-[second adenosine deaminase]-COOH;

NH ₂ -[Cas9]-[first adenosine deaminase]-[second adenosine deaminase]-COOH;

NH ₂ -[second adenosine deaminase]-[first adenosine deaminase]-[Cas9]-COOH;

NH ₂ -[second adenosine deaminase]-[Cas9]-[first adenosine deaminase]-COOH;

NH ₂ -[Cas9]-[second adenosine deaminase]-[first adenosine deaminase]-COOH;

[00362] In some embodiments, the fusion proteins provided herein do not comprise a linker. In some embodiments, a linker is present between one or more of the domains or proteins (e.g., first adenosine deaminase, second adenosine deaminase, and/or napDNAbp). In some embodiments, the“-” used in the general architecture above indicates the presence of an optional linker.

[00363] In some embodiments, a fusion protein comprising a first adenosine deaminase, a second adenosine deaminase, and a Cas9 domain further comprise a NLS. Exemplary fusion proteins comprising a first adenosine deaminase, a second adenosine deaminase, a napDNAbp, and an NLS are shown as follows: NH ₂ -[NLS]-[first adenosine deaminase]-[second adenosine deaminase]-[Cas9]-COOH;

NH ₂ -[first adenosine deaminase]-[NLS]-[second adenosine deaminase]-[Cas9]-COOH;

NH ₂ -[first adenosine deaminase]-[second adenosine deaminase]-[NLS]-[Cas9]-COOH;

NH ₂ -[first adenosine deaminase]-[second adenosine deaminase]-[Cas9]-[NLS]-COOH;

NH ₂ -[NLS]-[first adenosine deaminase]-[Cas9]-[second adenosine deaminase]-COOH;

NH ₂ -[first adenosine deaminase]-[NLS]-[Cas9]-[second adenosine deaminase]-COOH;

NH ₂ -[first adenosine deaminase]-[Cas9]-[NLS]-[second adenosine deaminase]-COOH;

NH ₂ -[first adenosine deaminase]-[Cas9]-[second adenosine deaminase]-[NLS]-COOH;

NH ₂ -[NLS]-[Cas9]-[first adenosine deaminase]-[second adenosine deaminase]-COOH;

NH ₂ -[Cas9]-[NLS]-[first adenosine deaminase]-[second adenosine deaminase]-COOH;

NH ₂ -[Cas9]-[first adenosine deaminase]-[NLS]-[second adenosine deaminase]-COOH;

NH ₂ -[Cas9]-[first adenosine deaminase]-[second adenosine deaminase]-[NLS]-COOH;

NH ₂ -[NLS]-[second adenosine deaminase]-[first adenosine deaminase]-[Cas9]-COOH;

NH ₂ -[second adenosine deaminase]-[NLS]-[first adenosine deaminase]-[Cas9]-COOH;

NH ₂ -[second adenosine deaminase]-[first adenosine deaminase]-[NLS]-[Cas9]-COOH;

NH ₂ -[second adenosine deaminase]-[first adenosine deaminase]-[Cas9]-[NLS]-COOH;

NH ₂ -[NLS]-[second adenosine deaminase]-[Cas9]-[first adenosine deaminase]-COOH;

NH ₂ -[second adenosine deaminase]-[NLS]-[Cas9]-[first adenosine deaminase]-COOH;

NH ₂ -[second adenosine deaminase]-[Cas9]-[NLS]-[first adenosine deaminase]-COOH;

NH ₂ -[second adenosine deaminase]-[Cas9]-[first adenosine deaminase]-[NLS]-COOH;

NH ₂ -[NLS]-[Cas9]-[second adenosine deaminase]-[first adenosine deaminase]-COOH;

NH ₂ -[Cas9]-[NLS]-[second adenosine deaminase]-[first adenosine deaminase]-COOH;

NH ₂ -[Cas9]-[second adenosine deaminase]-[NLS]-[first adenosine deaminase]-COOH;

NH ₂ -[Cas9]-[second adenosine deaminase]-[first adenosine deaminase]-[NLS]-COOH;

[00364] In some embodiments, the fusion proteins provided herein do not comprise a linker. In some embodiments, a linker is present between one or more of the domains or proteins (e.g., first adenosine deaminase, second adenosine deaminase, Cas9 domain, and/or NLS). In some embodiments, the“-” used in the general architecture above indicates the presence of an optional linker.

[00365] In some embodiments, the fusion protein comprises a Cas9 domain fused to one or more adenosine deaminase domains (e.g., a first adenosine deaminase and a second adenosine deaminase), wherein the fusion protein comprises or consists of the amino acid sequence of SEQ ID NO: 127. In some embodiments, the fusion protein comprises the amino acid sequence of SEQ ID NO: 128. In some embodiments, the fusion protein is the amino acid sequence of SEQ ID NO: 129. In some embodiments, the Cas9 domain of SEQ ID NOs: 127-129 is replaced with any of the Cas9 domains provided herein.

[00366] xCas9(3.7)–ABE: (ecTadA(wt)–linker(32 aa)–ecTadA*(7.10)–linker(32 aa)–nxCas9(3.7)– NLS):

[00368] ABE7.10: ecTadA _(wild-type) -(SGGS) ₂ -XTEN-(SGGS) ₂ - ecTadA _{(W23R_H36L_P48A_R51L_L84F_A106V_D108N_H123Y_S146C_D147Y _R152P_E155V_I156F_K157N)} -(SGGS) ₂ -XTEN- (SGGS) C 9 SGGS NLS

[00370] In some embodiments, the fusion proteins provided herein comprising one or more adenosine deaminase domains and a Cas9 domain exhibit an increased activity on a target sequence that does not comprise the canonical PAM (5¢-NGG-3¢) at its 3ʹ end as compared to a fusion protein comprising Streptococcus pyogenes Cas9 as provided by SEQ ID NO: 2. In some embodiments, the fusion protein exhibits an activity on a target sequence having a 3ʹ end that is not directly adjacent to the canonical PAM sequence (5¢-NGG-3¢) that is at least 2-fold, at least 3-fold, at least 4-fold, at least 5-fold, at least 10-fold, at least 50-fold, at least 100-fold, at least 500-fold, at least 1,000-fold, at least 5,000-fold, at least 10,000-fold, at least 50,000-fold, at least 100,000-fold, at least 500,000-fold, or at least 1,000,000-fold increased as compared to the activity of a fusion protein comprising

Streptococcus pyogenes Cas9 as provided by SEQ ID NO: 2 on the same target sequence. In some embodiments, the 3ʹ end of the target sequence is directly adjacent to a sequence selected from the group consisting of NGT, NGA, NGC, and NNG, wherein N is an A, G, T, or C. In some

embodiments, the 3ʹ end of the target sequence is directly adjacent to a sequence selected from the group consisting of CGG, AGT, TGG, AGT, CGT, GGG, CGT, TGT, GGT, AGC, CGC, TGC, GGC, AGA, CGA, TGA, GGA, GAA, GAT, and CAA. In some embodiments, the fusion protein activity is measured by a nuclease assay, a deamination assay, a transcriptional activation assay, or high- throughput sequencing. In some embodiments, the transcriptional activation assay is a GFP activation assay. In some embodiments, high-throughput sequencing is used to measure indel formation.

[00371] It should be appreciated that the fusion proteins of the present disclosure may comprise one or more additional features. For example, in some embodiments, the fusion protein may comprise cytoplasmic localization sequences, export sequences, such as nuclear export sequences, or other localization sequences, as well as sequence tags that are useful for solubilization, purification, or detection of the fusion proteins. Suitable protein tags provided herein include, but are not limited to, biotin carboxylase carrier protein (BCCP) tags, myc-tags, calmodulin-tags, FLAG-tags,

hemagglutinin (HA)-tags, polyhistidine tags, also referred to as histidine tags or His-tags, maltose binding protein (MBP)-tags, nus-tags, glutathione-S-transferase (GST)-tags, green fluorescent protein (GFP)-tags, thioredoxin-tags, S-tags, Softags (e.g., Softag 1, Softag 3), strep-tags, biotin ligase tags, FlAsH tags, V5 tags, and SBP-tags. Additional suitable sequences will be apparent to those of ordinary skill in the art. In some embodiments, the fusion protein comprises one or more His tags.

[00372] Additional suitable strategies for generating fusion proteins comprising a napDNAbp (e.g., a Cas9 domain) and a nucleic acid editing domain (e.g., a deaminase domain) will be apparent to those of ordinary skill in the art based on this disclosure in combination with the general knowledge in the art. Suitable strategies for generating fusion proteins according to aspects of this disclosure using linkers or without the use of linkers will also be apparent to those of ordinary skill in the art in view of the instant disclosure and the knowledge in the art. For example, Gilbert et al., CRISPR-mediated modular RNA-guided regulation of transcription in eukaryotes. Cell.2013; 154(2):442-51, showed that C-terminal fusions of Cas9 with VP64 using 2 NLS’s as a linker, can be employed for transcriptional activation. Mali et al. (CAS9 transcriptional activators for target specificity screening and paired nickases for cooperative genome engineering. Nat Biotechnol.2013; 31(9):833-8), reported that C-terminal fusions with VP64 without linker can be employed for transcriptional activation. And Maeder et al. (CRISPR RNA-guided activation of endogenous human genes. Nat Methods.2013; 10: 977-979), reported that C-terminal fusions with VP64 using a GGGGS (SEQ ID NO: 94) linker can be used as transcriptional activators. Recently, dCas9- FokI nuclease fusions have successfully been generated and exhibit improved enzymatic specificity as compared to the parental Cas9 enzyme (In Guilinger JP, Thompson DB, Liu DR. Fusion of catalytically inactive Cas9 to FokI nuclease improves the specificity of genome modification. Nat. Biotechnol.2014; 32(6): 577-82; and in Tsai SQ, et al. Dimeric CRISPR RNA-guided FokI nucleases for highly specific genome editing. Nat Biotechnol.2014; 32(6):569-76. PMID: 24770325 a SGSETPGTSESATPES (SEQ ID NO: 89) or a GGGGS (SEQ ID NO: 94) linker was used in FokI-dCas9 fusion proteins, respectively).

[00373] In some embodiments, the Cas9 fusion protein comprises: (i) Cas9 domain; and (ii) a transcriptional activator domain. In some embodiments, the transcriptional activator domain comprises a VPR. VPR is a VP64-SV40-P65-RTA tripartite activator. In some embodiments, VPR comprises a VP64 amino acid sequence encoded by the nucleic acid sequence of SEQ ID NO: 85: ( Q )

[00374] In some embodiments, VPR comprises a VP64 amino acid sequence as set forth in SEQ ID NO: 86:

EASGSGRADALDDFDLDMLGSDALDDFDLDMLGSDALDDFDLDMLGSDALDDFDLDMLIN SR (SEQ ID NO: 86).

[00375] In some embodiments, VPR compises a VP64-SV40-P65-RTA amino acid sequence encoded

[00376] In some embodiments, VPR comprises a VP64-SV40-P65-RTA amino acid sequence as set forth in SEQ ID NO: 88:

(SEQ ID NO: 88).

[00377] Some aspects of this disclosure provide fusion proteins comprising a transcription activator. In some embodiments, the transcriptional activator is VPR. In some embodiments, the VPR comprises a wild type VPR or a VPR as set forth in SEQ ID NO: 88. In some embodiments, the VPR proteins provided herein include fragments of VPR and proteins homologous to a VPR or a VPR fragment. For example, in some embodiments, a VPR comprises a fragment of the amino acid sequence set forth in SEQ ID NO: 88. In some embodiments, a VPR comprises an amino acid sequence homologous to the amino acid sequence set forth in SEQ ID NO: 88 or an amino acid sequence homologous to a fragment of the amino acid sequence set forth in SEQ ID NO: 8. In some embodiments, proteins comprising VPR or fragments of VPR or homologs of VPR or VPR fragments are referred to as“VPR variants.” A VPR variant shares homology to VPR, or a fragment thereof. For example a VPR variant is at least about 70% identical, at least about 80% identical, at least about 90% identical, at least about 95% identical, at least about 96% identical, at least about 97% identical, at least about 98% identical, at least about 99% identical, at least about 99.5% identical, or at least about 99.9% to a wild type VPR or a VPR as set forth in SEQ ID NO: 88. In some embodiments, the VPR variant comprises a fragment of VPR, such that the fragment is at least about 70% identical, at least about 80% identical, at least about 90% identical, at least about 95% identical, at least about 96% identical, at least about 97% identical, at least about 98% identical, at least about 99% identical, at least about 99.5% identical, or at least about 99.9% to the corresponding fragment of wild type VPR or a VPR as set forth in SEQ ID NO: 88. In some embodiments, the VPR comprises the amino acid sequence set forth in SEQ ID NO: 88. In some embodiments, the VPR comprises an amino acid sequence encoded by the nucleotide sequence set forth in SEQ ID NO: 88.

[00378] In some embodiments, a VPR is a VP64-SV40-P65-RTA triple activator. In some embodiments, the VP64-SV40-P65-RTA comprises a VP64-SV40-P65-RTA as set forth in SEQ ID NO: 88. In some embodiments, the VP64-SV40-P65-RTA proteins provided herein include fragments of VP64-SV40-P65-RTA and proteins homologous to a VP64-SV40-P65-RTA or a VP64-SV40-P65- RTA fragment. For example, in some embodiments, a VP64-SV40-P65-RTA comprises a fragment of the amino acid sequence set forth in SEQ ID NO: 88. In some embodiments, a VP64-SV40-P65-RTA comprises an amino acid sequence homologous to the amino acid sequence set forth in SEQ ID NO: 88 or an amino acid sequence homologous to a fragment of the amino acid sequence set forth in SEQ ID NO: 88. In some embodiments, proteins comprising VP64-SV40-P65-RTA or fragments of VP64- SV40-P65-RTA or homologs of VP64-SV40-P65-RTA or VP64-SV40-P65-RTA fragments are referred to as“VP64-SV40-P65-RTA variants.” A VP64-SV40-P65-RTA variant shares homology to VP64-SV40-P65-RTA, or a fragment thereof. For example a VP64-SV40-P65-RTA variant is at least about 70% identical, at least about 80% identical, at least about 90% identical, at least about 95% identical, at least about 96% identical, at least about 97% identical, at least about 98% identical, at least about 99% identical, at least about 99.5% identical, or at least about 99.9% to a VP64-SV40- P65-RTA as set forth in SEQ ID NO: 88. In some embodiments, the VP64-SV40-P65-RTA variant comprises a fragment of VP64-SV40-P65-RTA, such that the fragment is at least about 70% identical, at least about 80% identical, at least about 90% identical, at least about 95% identical, at least about 96% identical, at least about 97% identical, at least about 98% identical, at least about 99% identical, at least about 99.5% identical, or at least about 99.9% to a fragment of a VP64-SV40-P65-RTA as set forth in SEQ ID NO: 88. In some embodiments, the VP64-SV40-P65-RTA comprises the amino acid sequence set forth in SEQ ID NO: 88. In some embodiments, the VP64-SV40-P65-RTA comprises an amino acid sequence encoded by the nucleotide sequence set forth in SEQ ID NO: 87.

[00379] In some embodiments, the fusion protein comprises the nucleic acid sequence of SEQ ID NO: 87.

[00380] dCas9–VPR (dCas9(3.7)–NLS–linker(22aa)–VP64–linker(4aa)–NLS� ��p65AD–linker(6aa)-

[00381] Some aspects of this disclosure provide fusion proteins comprising a Cas9 domain as provided herein that is fused to a second protein, or a“fusion partner”, such as a nucleic acid editing domain, thus forming a fusion protein. In some embodiments, the nucleic acid editing domain is fused to the N-terminus of the Cas9 domain. In some embodiments, the nucleic acid editing domain is fused to the C-terminus of the Cas9 domain. In some embodiments, the Cas9 domain and the nucleic acid editing domain are fused to each other via a linker. Suitable strategies for generating fusion proteins according to aspects of this disclosure using linkers or without the use of linkers will also be apparent to those of skill in the art in view of the instant disclosure and the knowledge in the art. For example, Gilbert et al., CRISPR-mediated modular RNA-guided regulation of transcription in eukaryotes. Cell. 2013; 154(2):442-51, showed that C-terminal fusions of Cas9 with VP64 using 2 NLS’s as a linker (SPKKKRKVEAS), can be employed for transcriptional activation. Mali et al., CAS9 transcriptional activators for target specificity screening and paired nickases for cooperative genome engineering. Nat Biotechnol.2013; 31(9):833-8, reported that C-terminal fusions with VP64 without linker can be employed for transcriptional activation. Maeder et al., CRISPR RNA-guided activation of endogenous human genes. Nat Methods.2013; 10: 977-979, reported that C-terminal fusions with VP64 using a GGGGS (SEQ ID NO: 94) linker can be used as transcriptional activators. Recently, dCas9- FokI nuclease fusions have successfully been generated and exhibit improved enzymatic specificity as compared to the parental Cas9 enzyme (In Guilinger JP, Thompson DB, Liu DR. Fusion of catalytically inactive Cas9 to FokI nuclease improves the specificity of genome modification. Nat. Biotechnol.2014; 32(6): 577-82, and in Tsai SQ, Wyvekens N, Khayter C, Foden JA, Thapar V, Reyon D, Goodwin MJ, Aryee MJ, Joung JK. Dimeric CRISPR RNA-guided FokI nucleases for highly specific genome editing. Nat Biotechnol.2014; 32(6):569-76. PMID: 24770325 a

SGSETPGTSESATPES (SEQ ID NO: 89) or a GGGGS _n (SEQ ID NO: 95) linker was used in FokI- dCas9 fusion proteins, respectively).

[00382] In some embodiments, the second protein in the fusion protein (i.e., the fusion partner) comprises a nucleic acid editing domain. Such a nucleic acid editing domain may be, without limitation, a nuclease, a nickase, a recombinase, a deaminase, a methyltransferase, a methylase, an acetylase, or an acetyltransferase. Non-limiting exemplary nucleic acid editing domains that may be used in accordance with this disclosure include cytidine deaminases and adenosine deaminases. In some embodiments, the nucleic acid editing domain is a deaminase domain. In some embodiments, the nucleic acid editing domain is a nuclease domain. In some embodiments, the nuclease domain is a FokI DNA cleavage domain. In some embodiments, this disclosure provides dimers of the fusion proteins provided herein, e.g., dimers of fusion proteins may include a dimerizing nuclease domain. In some embodiments, the nucleic acid editing domain is a nickase domain. In some embodiments, the nucleic acid editing domain is a recombinase domain. In some embodiments, the nucleic acid editing domain is a methyltransferase domain. In some embodiments, the nucleic acid editing domain is a methylase domain. In some embodiments, the nucleic acid editing domain is an acetylase domain. In some embodiments, the nucleic acid editing domain is an acetyltransferase domain. Additional nucleic acid editing domains would be apparent to a person of ordinary skill in the art based on this disclosure and knowledge in the field and are within the scope of this disclosure. In other embodiments, the second protein comprises a domain that modulates transcriptional activity. Such transcriptional modulating domains may be, without limitation, a transcriptional activator or transcriptional repressor domain.

Guide RNA

[00383] In various embodiments, the base editors described herein may be complexed, bound, or otherwise associated with (e.g., via any type of covalent or non-covalent bond) one or more guide sequences, i.e., the sequence which becomes associated or bound to the base editor and directs its localization to a specific target sequence having complementarity to the guide sequence or a portion thereof. The particular design embodiments of a guide sequence will depend upon the nucleotide sequence of a genomic target site of interest (i.e., the desired site to be edited) and the type of napDNAbp (e.g., type of Cas protein) present in the base editor, among other factors, such as PAM sequence locations, percent G/C content in the target sequence, the degree of microhomology regions, secondary structures, etc.

[00384] In general, a guide sequence is any polynucleotide sequence having sufficient

complementarity with a target polynucleotide sequence to hybridize with the target sequence and direct sequence-specific binding of a napDNAbp (e.g., a Cas9, Cas9 homolog, or Cas9 variant) to the target sequence. In some embodiments, the degree of complementarity between a guide sequence and its corresponding target sequence, when optimally aligned using a suitable alignment algorithm, is about or more than about 50%, 60%, 75%, 80%, 85%, 90%, 95%, 97.5%, 99%, or more. Optimal alignment may be determined with the use of any suitable algorithm for aligning sequences, non- limiting example of which include the Smith-Waterman algorithm, the Needleman-Wunsch algorithm, algorithms based on the Burrows-Wheeler Transform (e.g. the Burrows Wheeler Aligner), ClustalW, Clustal X, BLAT, Novoalign (Novocraft Technologies, ELAND (Illumina, San Diego, Calif.), SOAP (available at soap.genomics.org.cn), and Maq (available at maq.sourceforge.net). In some embodiments, a guide sequence is about or more than about 5, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 35, 40, 45, 50, 75, or more nucleotides in length.

[00385] In some embodiments, a guide sequence is less than about 75, 50, 45, 40, 35, 30, 25, 20, 15, 12, or fewer nucleotides in length. The ability of a guide sequence to direct sequence-specific binding of a base editor to a target sequence may be assessed by any suitable assay. For example, the components of a base editor, including the guide sequence to be tested, may be provided to a host cell having the corresponding target sequence, such as by transfection with vectors encoding the components of a base editor disclosed herein, followed by an assessment of preferential cleavage within the target sequence, such as by Surveyor assay as described herein. Similarly, cleavage of a target polynucleotide sequence may be evaluated in a test tube by providing the target sequence, components of a base editor, including the guide sequence to be tested and a control guide sequence different from the test guide sequence, and comparing binding or rate of cleavage at the target sequence between the test and control guide sequence reactions. Other assays are possible, and will occur to those skilled in the art.

[00386] A guide sequence may be selected to target any target sequence. In some embodiments, the target sequence is a sequence within a genome of a cell. Exemplary target sequences include those that are unique in the target genome. For example, for the S. pyogenes Cas9, a unique target sequence in a genome may include a Cas9 target site of the form MMMMMMMMNNNNNNNNNNNNXGG (SEQ ID NO: 134) where NNNNNNNNNNNNXGG (N is A, G, T, or C; and X can be anything) (SEQ ID NO: 135) has a single occurrence in the genome. A unique target sequence in a genome may include an S. pyogenes Cas9 target site of the form MMMMMMMMMNNNNNNNNNNNXGG (SEQ ID NO: 134) where NNNNNNNNNNNXGG (N is A, G, T, or C; and X can be anything) (SEQ ID NO: 135) has a single occurrence in the genome. For the S. thermophilus CRISPR1Cas9, a unique target sequence in a genome may include a Cas9 target site of the form MMMMMMMMNNNNNNNNNNNNXXAGAAW (SEQ ID NO: 138) where NNNNNNNNNNNNXXAGAAW (N is A, G, T, or C; X can be anything; and W is A or T) (SEQ ID NO: 139) has a single occurrence in the genome. A unique target sequence in a genome may include an S. thermophilus CRISPR 1 Cas9 target site of the form

MMMMMMMMMNNNNNNNNNNNXXAGAAW (SEQ ID NO: 140) where NNNNNNNNNNNXXAGAAW (N is A, G, T, or C; X can be anything; and W is A or T) (SEQ ID NO: 140) has a single occurrence in the genome. For the S. pyogenes Cas9, a unique target sequence in a genome may include a Cas9 target site of the form MMMMMMMMNNNNNNNNNNNNXGGXG (SEQ ID NO: 142) where

NNNNNNNNNNNNXGGXG (N is A, G, T, or C; and X can be anything) (SEQ ID NO: 142) has a single occurrence in the genome. A unique target sequence in a genome may include an S. pyogenes Cas9 target site of the form MMMMMMMMMNNNNNNNNNNNXGGXG (SEQ ID NO: 144) where

NNNNNNNNNNNXGGXG (N is A, G, T, or C; and X can be anything) (SEQ ID NO: 145) has a single occurrence in the genome. In each of these sequences“M” may be A, G, T, or C, and need not be considered in identifying a sequence as unique.

[00387] In some embodiments, a guide sequence is selected to reduce the degree of secondary structure within the guide sequence. Secondary structure may be determined by any suitable polynucleotide folding algorithm. Some programs are based on calculating the minimal Gibbs free energy. An example of one such algorithm is mFold, as described by Zuker & Stiegler (Nucleic Acids Res.9 (1981), 133-148). Another example folding algorithm is the online webserver RNAfold, developed at Institute for Theoretical Chemistry at the University of Vienna, using the centroid structure prediction algorithm (see, e.g., A. R. Gruber et al., 2008, Cell 106(1): 23-24; and PA Carr & GM Church, 2009, Nature Biotechnology 27(12): 1151-62). Additional algorithms may be found in Chuai, G. et al., DeepCRISPR: optimized CRISPR guide RNA design by deep learning, Genome Biol. 19:80 (2018), and U.S. application Ser. No.61/836,080, the entireties of each of which are incorporated herein by reference.

[00388] The guide sequence is linked to a tracr mate sequence which in turn hybridizes to a tracr sequence. A tracr mate sequence includes any sequence that has sufficient complementarity with a tracr sequence to promote one or more of: (1) excision of a guide sequence flanked by tracr mate sequences in a cell containing the corresponding tracr sequence; and (2) formation of a complex at a target sequence, wherein the complex comprises the tracr mate sequence hybridized to the tracr sequence. In general, degree of complementarity is with reference to the optimal alignment of the tracr mate sequence and tracr sequence, along the length of the shorter of the two sequences. Optimal alignment may be determined by any suitable alignment algorithm, and may further account for secondary structures, such as self-complementarity within either the tracr sequence or tracr mate sequence. In some embodiments, the degree of complementarity between the tracr sequence and tracr mate sequence along the length of the shorter of the two when optimally aligned is about or more than about 25%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 97.5%, 99%, or higher. In some embodiments, the tracr sequence is about or more than about 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 25, 30, 40, 50, or more nucleotides in length. In some embodiments, the tracr sequence and tracr mate sequence are contained within a single transcript, such that hybridization between the two produces a transcript having a secondary structure, such as a hairpin. Preferred loop forming sequences for use in hairpin structures are four nucleotides in length, and most preferably have the sequence GAAA. However, longer or shorter loop sequences may be used, as may alternative sequences. The sequences preferably include a nucleotide triplet (for example, AAA), and an additional nucleotide (for example C or G). Examples of loop forming sequences include CAAA and AAAG. In an embodiment of the disclosure, the transcript or transcribed polynucleotide sequence has at least two or more hairpins. In certain embodiments, the transcript has two, three, four or five hairpins. In a further embodiment of the disclosure, the transcript has at most five hairpins. In some embodiments, the single transcript further includes a transcription termination sequence; preferably this is a polyT sequence, for example six T nucleotides. Further non-limiting examples of single polynucleotides comprising a guide sequence, a tracr mate sequence, and a tracr sequence are as follows (listed 5¢ to 3¢), where“N” represents a base of a guide sequence, the first block of lower case letters represent the tracr mate sequence, and the second block of lower case letters represent the tracr sequence, and the final poly-T sequence represents the transcription terminator:

[00389] In some embodiments, sequences (1) to (3) are used in combination with Cas9 from S. thermophilus CRISPR1. In some embodiments, sequences (4) to (6) are used in combination with Cas9 from S. pyogenes. In some embodiments, the tracr sequence is a separate transcript from a transcript comprising the tracr mate sequence.

It will be apparent to those of skill in the art that in order to target any of the fusion proteins comprising a Cas9 domain and a thymine alkyltransferase, as disclosed herein, to a target site, e.g., a site comprising a point mutation to be edited, it is typically necessary to co-express the fusion protein together with a guide RNA, e.g., an sgRNA. As explained in more detail elsewhere herein, a guide RNA typically comprises a tracrRNA framework allowing for Cas9 binding, and a guide sequence, which confers sequence specificity to the Cas9:nucleic acid editing enzyme/domain fusion protein. In some embodiments, the guide RNA comprises a structure 5¢-[guide sequence]- guuuuagagcuagaaauagcaaguuaaaauaaggcuaguccguuaucaacuugaaaaagu ggcaccga gucggugcuuuuu-3¢ (SEQ ID NO: 152), wherein the guide sequence comprises a sequence that is complementary to the target sequence. See U.S. Publication No.2015/0166981, published June 18, 2015, the disclosure of which is incorporated by reference herein in its entirety. The guide sequence is typically 20 nucleotides long.

[00390] The sequences of suitable guide RNAs for targeting Cas9:nucleic acid editing enzyme/domain fusion proteins to specific genomic target sites will be apparent to those of skill in the art based on the instant disclosure. Such suitable guide RNA sequences typically comprise guide sequences that are complementary to a nucleic sequence within 50 nucleotides upstream or downstream of the target nucleotide to be edited. Some exemplary guide RNA sequences suitable for targeting any of the provided fusion proteins to specific target sequences are provided herein. Additional guide sequences are are well known in the art and can be used with the base editors described

herein.Additional exemplary guide sequences are disclosed in, for example, Jinek M., et al., Science 337:816-821(2012); Mali P, Esvelt KM & Church GM (2013) Cas9 as a versatile tool for engineering biology, Nature Methods, 10, 957-963; Li JF et al., (2013) Multiplex and homologous recombination- mediated genome editing in Arabidopsis and Nicotiana benthamiana using guide RNA and Cas9, Nature Biotechnology, 31, 688-691; Hwang, W.Y. et al., Efficient genome editing in zebrafish using a CRISPR-Cas system, Nature Biotechnology 31, 227-229 (2013); Cong L et al., (2013) Multiplex genome engineering using CRIPSR/Cas systems, Science, 339, 819-823; Cho SW et al., (2013) Targeted genome engineering in human cells with the Cas9 RNA-guided endonuclease, Nature Biotechnology, 31, 230-232; Jinek, M. et al., RNA-programmed genome editing in human cells, eLife 2, e00471 (2013); Dicarlo, J.E. et al., Genome engineering in Saccharomyces cerevisiae using CRISPR-Cas systems. Nucleic Acid Res. (2013); Briner AE et al., (2014) Guide RNA functional modules direct Cas9 activity and orthogonality, Mol Cell, 56, 333-339, the entire contents of each of which are herein incorporated by reference.

Base editor complexes

[00391] Further provided herein are complexes comprising (i) any of the fusion proteins provided herein, and (ii) a guide RNA bound to the Cas9 domain of the fusion protein. Without wishing to be bound by any particular theory, these fusion proteins can be directed by designing a suitable guide RNA to specifically and efficiently target single point mutations in a genome without introducing double-stranded DNA breaks or requiring homology directed repair (HDR). However, the suitability of a target site for base editing (e.g., a point mutation in the genome) is dependent on the presence of a suitably positioned PAM. The broaden PAM compatibility of the Cas9 domains provided herein has the potential to expand the targeting scope of base editors to those target sites that do not lie within approximately 15 nucleotides of a canonical 5¢-NGG-3¢ PAM sequence. A person of ordinary skill in the art will be able to design a suitable guide RNA (gRNA) sequence to target a desired point mutation based on this disclosure and knowledge in the field. In addition, these fusion proteins comprising a Cas9 domain generate fewer insertions and deletions (indels) and exhibit reduced off-target activity compared to fusion proteins (e.g., base editors) comprising a Cas9 domain that can only recognize the canonical 5¢-NGG-3¢ PAM sequence.

[00392] In some embodiments, the guide RNA is about 15-100 nucleotides long and comprises a sequence of at least 10 contiguous nucleotides that is complementary to a target sequence. In some embodiments, the guide RNA is 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, or 50 nucleotides long. In some embodiments, the guide RNA comprises a sequence of 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, or 40 contiguous nucleotides that is complementary to a target sequence. In some embodiments, the target sequence is a DNA sequence. In some embodiments, the target sequence is in the genome of an organism. In some embodiments, the organism is a prokaryote. In some embodiments, the prokaryote is a bacterium. In some embodiments, the bacterium is E. coli. In some embodiments, the organism is a eukaryote. In some embodiments, the organism is a plant or fungus. In some embodiments, the organism is a vertebrate. In some embodiments, the vertebrate is a mammal. In some embodiments, the mammal is a human. In some embodiments, the organism is a cell. In some embodiments, the cell is a human cell. In some embodiments, the cell is a HEK293T or U2OS cell.

[00393] In some embodiments, the target sequence comprises a sequence associated with a disease or disorder. In some embodiments, the target sequence comprises a point mutation associated with a disease or disorder. In some embodiments, the target sequence comprises a T®C point mutation. In some embodiments, the complex deaminates the target C point mutation, wherein the deamination results in a sequence that is not associated with a disease or disorder. In some embodiments, the target C point mutation is present in the DNA strand that is not complementary to the guide RNA. In some embodiments, the target sequence comprises a T®A point mutation. In some embodiments, the complex deaminates the target A point mutation, and wherein the deamination results in a sequence that is not associated with a disease or disorder. In some embodiments, the target A point mutation is present in the DNA strand that is not complementary to the guide RNA.

[00394] In some embodiments, the complex edits a point mutation in the target sequence. In some embodiments, the point mutation is located between about 10 to about 20 nucleotides upstream of the PAM in the target sequence. In some embodiments, the point mutation is located between about 13 to about 17 nucleotides upstream of the PAM in the target sequence. In some embodiments, the point mutation is about 13 nucleotides upstream of the PAM. In some embodiments, the point mutation is about 14 nucleotides upstream of the PAM. In some embodiments, the point mutation is about 15 nucleotides upstream of the PAM. In some embodiments, the point mutation is about 16 nucleotides upstream of the PAM. In some embodiments, the point mutation is about 17 nucleotides upstream of the PAM.

[00395] In some embodiments, the complex exhibits increased deamination efficiency of a point mutation in a target sequence that does not comprise the canonical PAM (5¢-NGG-3¢) at its 3ʹ end as compared to the deamination efficiency of a complex comprising Streptococcus pyogenes Cas9 as provided by SEQ ID NO: 2. In some embodiments, the complex exhibits increased deamination efficiency of a point mutation in a target sequence having a 3ʹ end that is not directly adjacent to the canonical PAM sequence (5¢-NGG-3¢) that is at least 2-fold, at least 3-fold, at least 4-fold, at least 5- fold, at least 10-fold, at least 50-fold, at least 100-fold, at least 500-fold, at least 1,000-fold, at least 5,000-fold, at least 10,000-fold, at least 50,000-fold, at least 100,000-fold, at least 500,000-fold, or at least 1,000,000-fold increased as compared to the deamination efficiency of complex comprising the Streptococcus pyogenes Cas9 as provided by SEQ ID NO: 2 on the same target sequence. In some embodiments, the 3ʹ end of the target sequence is directly adjacent to a sequence selected from the group consisting of NGT, NGA, NGC, and NNG, wherein N is an A, G, T, or C. In some

embodiments, the 3ʹ end of the target sequence is directly adjacent to a sequence selected from the group consisting of CGG, AGT, TGG, AGT, CGT, GGG, CGT, TGT, GGT, AGC, CGC, TGC, GGC, AGA, CGA, TGA, GGA, GAA, GAT, and CAA. In some embodiments, deamination activity is measured using high-throughput sequencing.

[00396] In some embodiments, the complex produces fewer indels in a target sequence that does not comprise the canonical PAM (5¢-NGG-3¢) at its 3ʹ end as compared to the amount of indels produced by a complex comprising Streptococcus pyogenes Cas9 as provided by SEQ ID NO: 2. In some embodiments, the complex produces fewer indels in a target sequence having a 3ʹ end that is not directly adjacent to the canonical PAM sequence (5¢-NGG-3¢) that is at least 2-fold, at least 3-fold, at least 4-fold, at least 5-fold, at least 10-fold, at least 50-fold, at least 100-fold, at least 500-fold, at least 1,000-fold, at least 5,000-fold, at least 10,000-fold, at least 50,000-fold, at least 100,000-fold, at least 500,000-fold, or at least 1,000,000-fold lower as compared to the amount of indels produced by a complex comprising Streptococcus pyogenes Cas9 as provided by SEQ ID NO: 2 on the same target sequence. In some embodiments, the 3ʹ end of the target sequence is directly adjacent to a sequence selected from the group consisting of NGT, NGA, NGC, and NNG, wherein N is an A, G, T, or C. In some embodiments, the 3ʹ end of the target sequence is directly adjacent to a sequence selected from the group consisting of CGG, AGT, TGG, AGT, CGT, GGG, CGT, TGT, GGT, AGC, CGC, TGC, GGC, AGA, CGA, TGA, GGA, GAA, GAT, and CAA. In some embodiments, indels are measured using high-throughput sequencing.

[00397] In some embodiments, the complex exhibits a decreased off-target activity as compared to the off-target activity of a complex comprising Streptococcus pyogenes Cas9 as provided by SEQ ID NO: 2. In some embodiments, the off-target activity of the complex is at least 2-fold, at least 3-fold, at least 4-fold, at least 5-fold, at least 10-fold, at least 50-fold, at least 100-fold, at least 500-fold, at least 1,000-fold, at least 5,000-fold, at least 10,000-fold, at least 50,000-fold, at least 100,000-fold, at least 500,000-fold, or at least 1,000,000-fold decreased as compared to the off-target activity of a complex comprising Streptococcus pyogenes Cas9 as provided by SEQ ID NO: 2. In some embodiments, the off-target activity is determined using a genome-wide off-target analysis. In some embodiments, the off-target activity is determined using GUIDE-seq.

Methods of using base editors

[00398] Some aspects of this disclosure provide methods of using the Cas9 domains, fusion proteins, or complexes provided herein.

[00399] In one aspect, provided herein are methods comprising contacting a nucleic acid molecule (a) with any of the Cas9 domains or fusion proteins provided herein, and with at least one guide RNA, wherein the guide RNA is about 15-100 nucleotides long and comprises a sequence of at least 10 contiguous nucleotides that is complementary to a target sequence in the nucleic acid molecule; or (b) with a Cas9 domain, a fusion protein comprising a Cas9 domain, or a complex comprising a Cas9 domain, wherein the Cas9 domain is associated with at least one gRNA as provided herein. In some embodiments, the nucleic acid is present in a cell. In some embodiments, the nucleic acid is present in a subject. In some embodiments, the contacting is in vitro. In some embodiments, the contacting is in vivo in a subject.

[00400] In another aspect, provided herein are methods comprising contacting a cell (a) with any of the Cas9 domains or fusion proteins provided herein, and with at least one guide RNA, wherein the guide RNA is about 15-100 nucleotides long and comprises a sequence of at least 10 contiguous nucleotides that is complementary to a target sequence in the nucleic acid molecule; or (b) with a Cas9 domain, a fusion protein comprising a Cas9 domain, or a complex comprising a Cas9 domain, wherein the Cas9 domain is associated with at least one gRNA as provided herein. In some embodiments, the contacting is in vitro. In some embodiments, the contacting is in vivo in a subject. In some embodiments, the cell is a prokaryotic cell. In some embodiments, the prokaryotic cell is a bacterium. In some embodiments, the bacterium is E. coli. In some embodiments, the cell is a eukaryotic cell. In some embodiments, the eukaryotic cell is a mammalian cell. In some embodiments, the mammalian cell is a human cell. In some embodiments, the cell is a plant or fungal cell.

[00401] In another aspect, provided herein are methods for administering to a subject (a) any of the Cas9 domains or fusion proteins provided herein, and at least one guide RNA, wherein the guide RNA is about 15-100 nucleotides long and comprises a sequence of at least 10 contiguous nucleotides that is complementary to a target sequence in the nucleic acid molecule; or (b) a Cas9 domain, a fusion protein comprising a Cas9 domain, or a complex comprising a Cas9 domain, wherein the Cas9 domain is associated with at least one gRNA as provided herein. In some embodiments, an effective amount of the Cas9 domain, fusion protein, or complex is administered to the subject. In some embodiments, the effective amount is an amount effective for treating a disease or disorder, wherein the disease comprises one or more point mutations in a nucleic acid sequence associated with the disease or disorder. [00402] In some embodiments, the 3ʹ end of the target sequence is not immediately adjacent to the canonical PAM sequence (5¢-NGG-3¢). In some embodiments, the 3ʹ end of the target sequence is directly adjacent to a sequence selected from the group consisting of NGT, NGA, NGC, and NNG, wherein N is an A, G, T, or C. In some embodiments, the 3ʹ end of the target sequence is directly adjacent to a sequence selected from the group consisting of CGG, AGT, TGG, AGT, CGT, GGG, CGT, TGT, GGT, AGC, CGC, TGC, GGC, AGA, CGA, TGA, GGA, GAA, GAT, and CAA.

[00403] In some embodiments, the target sequence comprises a sequence associated with a disease or disorder. In some embodiments, the target sequence comprises a point mutation associated with a disease or disorder. In some embodiments, the activity of the Cas9 domain, the Cas9 fusion protein, or the complex results in a correction of the point mutation. In some embodiments, the target sequence comprises a T®C point mutation associated with a disease or disorder, wherein the deamination of the mutant C base results in a sequence that is not associated with a disease or disorder. In some embodiments, the target sequence comprises a A®G, wherein deamination of the C that is base- paired to the mutant G base results in a sequence that is not associated with a disease or disorder. In some embodiments, the target sequence encodes a protein and wherein the point mutation is in a codon and results in a change in the amino acid encoded by the mutant codon as compared to the wild-type codon. In some embodiments, the deamination of the mutant C results in a change of the amino acid encoded by the mutant codon. In some embodiments, the deamination of the mutant C results in the codon encoding the wild-type amino acid. In some embodiments, the target DNA sequence comprises a G®A point mutation associated with a disease or disorder, and wherein the deamination of the mutant A base results in a sequence that is not associated with a disease or disorder. In some embodiments, the target DNA sequence comprises a C®T point mutation associated with a disease or disorder, wherein deamination of the A that is base-paired with the mutant T results in a sequence that is not associated with a disease or disorder. In some embodiments, the target DNA sequence encodes a protein and wherein the point mutation is in a codon and results in a change in the amino acid encoded by the mutant codon as compared to the wild-type codon. In some embodiments, the deamination of the mutant A results in a change of the amino acid encoded by the mutant codon. In some embodiments, the deamination of the mutant A results in the codon encoding the wild-type amino acid. In some embodiments, the contacting is in vivo in a subject. In some embodiments, the subject has or has been diagnosed with a disease or disorder. In some embodiments, the disease or disorder is cystic fibrosis, phenylketonuria, epidermolytic hyperkeratosis (EHK), Charcot-Marie-Toot disease type 4J, neuroblastoma (NB), von Willebrand disease (vWD), myotonia congenital, hereditary renal amyloidosis, dilated cardiomyopathy (DCM), hereditary lymphedema, familial Alzheimer’s disease, HIV, Prion disease, chronic infantile neurologic cutaneous articular syndrome (CINCA), desmin-related myopathy (DRM), a neoplastic disease associated with a mutant PI3KCA protein, a mutant CTNNB1 protein, a mutant HRAS protein, or a mutant p53 protein. In some embodiments, the target sequence comprises a sequence located in a genomic locus. In some embodiments, the genomic locus is a HEK site. In some embodiments, the HEK site is HEK site 3 or HEK site 4. In some embodiments, the HEK site comprises a CGG, GGG, TGT, GGT, AGC, CGC, TGC, AGA, or TGA PAM sequence. In some embodiments, the genomic locus is EMX1. In some embodiments, the EMX1 locus comprises a GGG or CAA PAM sequence. In some embodiments, the genomic locus is VEGFA. In some embodiments, the VEGFA locus comprises a AGT, GGC, GGA, or GAT PAM sequence. In some embodiments, the genomic locus is FANCF. In some embodiments, the FANCF locus comprises a CGT, GAA, GAT, TGG, AGT, TGT, GGT, CGC, TGC, GGC, AGA, or TGA PAM sequence.

[00404] Some embodiments provide methods for using the Cas9 DNA editing fusion proteins provided herein. In some embodiments, the fusion protein is used to introduce a point mutation into a nucleic acid by deaminating a target nucleobase, e.g., a C or A residue. In some embodiments, the deamination of the target nucleobase results in the correction of a genetic defect, e.g., in the correction of a point mutation that leads to a loss of function in a gene product. In some embodiments, the genetic defect is associated with a disease or disorder, e.g., a lysosomal storage disorder or a metabolic disease, such as, for example, type I diabetes. In some embodiments, the methods provided herein are used to introduce a deactivating point mutation into a gene or allele that encodes a gene product that is associated with a disease or disorder. For example, in some embodiments, methods are provided herein that employ a fusion protein comprising a Cas9 domain (e.g., a base editor) to introduce a deactivating point mutation into an oncogene (e.g., in the treatment of a proliferative disease). A deactivating mutation may, in some embodiments, generate a premature stop codon in a coding sequence, which results in the expression of a truncated gene product, e.g., a truncated protein lacking the function of the full-length protein.

[00405] In some embodiments, the purpose of the methods provide herein is to restore the function of a dysfunctional gene via genome editing. The Cas9-deaminase fusion proteins provided herein can be validated for gene editing-based human therapeutics in vitro, e.g., by correcting a disease-associated mutation in human cell culture. It will be understood by the skilled artisan that the fusion proteins provided herein, e.g., the fusion proteins comprising a Cas9 domain and a cytidine deaminase domain can be used to correct any single T®C or A®G point mutation. In the first case, deamination of the mutant C back to U corrects the mutation, and in the latter case, deamination of the C that is base- paired with the mutant G, followed by a round of replication, corrects the mutation. The fusion proteins comprising a Cas9 domain and one or more adenosine deaminase domains can be used to correct any single G®A or C®T point mutation. In the first case, deamination of the mutant A to I corrects the mutation, and in the latter case, deamination of the A that is base-paired with the mutant T, followed by a round of replication, corrects the mutation.

[00406] An exemplary disease-relevant mutation that can be corrected by the provided fusion proteins in vitro or in vivo is the H1047R (A3140G) polymorphism in the PI3KCA protein. The

phosphoinositide-3-kinase, catalytic alpha subunit (PI3KCA) protein acts to phosphorylate the 3-OH group of the inositol ring of phosphatidylinositol. The PI3KCA gene has been found to be mutated in many different carcinomas, and thus it is considered to be a potent oncogene. ⁵⁰ In fact, the A3140G mutation is present in several NCI-60 cancer cell lines, such as, for example, the HCT116, SKOV3, and T47D cell lines, which are readily available from the American Type Culture Collection (ATCC). ⁵¹

[00407] In some embodiments, a cell carrying a mutation to be corrected, e.g., a cell carrying a point mutation, e.g., an A3140G point mutation in exon 20 of the PI3KCA gene, resulting in a H1047R substitution in the PI3KCA protein, is contacted with an expression construct encoding a Cas9 deaminase fusion protein and an appropriately designed sgRNA targeting the fusion protein to the respective mutation site in the encoding PI3KCA gene. Control experiments can be performed where the sgRNAs are designed to target the fusion enzymes to non-C residues that are within the PI3KCA gene. Genomic DNA of the treated cells can be extracted, and the relevant sequence of the PI3KCA genes PCR amplified and sequenced to assess the activities of the fusion proteins in human cell culture.

[00408] It will be understood that the example of correcting point mutations in PI3KCA is provided for illustration purposes and is not meant to limit the instant disclosure. The skilled artisan will understand that the instantly disclosed DNA-editing fusion proteins can be used to correct other point mutations and mutations associated with other cancers and with diseases other than cancer including other proliferative diseases.

[00409] The successful correction of point mutations in disease-associated genes and alleles opens up new strategies for gene correction with applications in therapeutics and basic research. Site-specific single-base modification systems like the disclosed fusions of Cas9 domains and deaminase domains also have applications in“reverse” gene therapy, where certain gene functions are purposely suppressed or abolished. In these cases, site-specifically mutating Trp (TGG), Gln (CAA and CAG), or Arg (CGA) residues to premature stop codons (TAA, TAG, TGA) can be used to abolish protein function in vitro, ex vivo, or in vivo. [00410] The instant disclosure provides methods for the treatment of a subject diagnosed with a disease associated with or caused by a point mutation that can be corrected by a fusion protein comprising a Cas9 domain and nucleic acid editing domain (e.g., a deaminase domain) provided herein. For example, in some embodiments, a method is provided that comprises administering to a subject having such a disease, e.g., a cancer associated with a PI3KCA point mutation as described above, an effective amount of a Cas9 deaminase fusion protein that corrects the point mutation or introduces a deactivating mutation into the disease-associated gene. In some embodiments, the disease is a proliferative disease. In some embodiments, the disease is a genetic disease. In some

embodiments, the disease is a neoplastic disease. In some embodiments, the disease is a metabolic disease. In some embodiments, the disease is a lysosomal storage disease. Other diseases that can be treated by correcting a point mutation or introducing a deactivating mutation into a disease-associated gene will be known to those of skill in the art, and the disclosure is not limited in this respect.

[00411] The instant disclosure provides methods for the treatment of additional diseases or disorders, e.g., diseases or disorders that are associated or caused by a point mutation that can be corrected by deaminase-mediated gene editing. Some such diseases are described herein, and additional suitable diseases that can be treated with the strategies and fusion proteins provided herein will be apparent to those of skill in the art based on the instant disclosure. Exemplary suitable diseases and disorders are listed below. It will be understood that the numbering of the specific positions or residues in the respective sequences depends on the particular protein and numbering scheme used. Numbering might be different, e.g., in precursors of a mature protein and the mature protein itself, and differences in sequences from species to species may affect numbering. One of skill in the art will be able to identify the respective residue in any homologous protein and in the respective encoding nucleic acid by methods well known in the art, e.g., by sequence alignment and determination of homologous residues. Exemplary suitable diseases and disorders include, without limitation, cystic fibrosis (see, e.g., Schwank et al., Functional repair of CFTR by CRISPR/Cas9 in intestinal stem cell organoids of cystic fibrosis patients. Cell stem cell.2013; 13: 653-658; and Wu et. al., Correction of a genetic disease in mouse via use of CRISPR-Cas9. Cell stem cell.2013; 13: 659-662, neither of which uses a deaminase fusion protein to correct the genetic defect); phenylketonuria– e.g., phenylalanine to serine mutation at position 835 (mouse) or 240 (human) or a homologous residue in phenylalanine hydroxylase gene (T>C mutation)– see, e.g., McDonald et al., Genomics.1997; 39:402-405;

Bernard-Soulier syndrome (BSS)– e.g., phenylalanine to serine mutation at position 55 or a homologous residue, or cysteine to arginine at residue 24 or a homologous residue in the platelet membrane glycoprotein IX (T>C mutation)– see, e.g., Noris et al., British Journal of Haematology. 1997; 97: 312-320, and Ali et al., Hematol.2014; 93: 381-384; epidermolytic hyperkeratosis (EHK)– e.g., leucine to proline mutation at position 160 or 161 (if counting the initiator methionine) or a homologous residue in keratin 1 (T>C mutation)– see, e.g., Chipev et al., Cell.1992; 70: 821-828, see also accession number P04264 in the UNIPROT database at www[dot]uniprot[dot]org; chronic obstructive pulmonary disease (COPD)– e.g., leucine to proline mutation at position 54 or 55 (if counting the initiator methionine) or a homologous residue in the processed form of a ₁ -antitrypsin or residue 78 in the unprocessed form or a homologous residue (T>C mutation)– see, e.g., Poller et al., Genomics.1993; 17: 740-743, see also accession number P01011 in the UNIPROT database; Charcot-Marie-Toot disease type 4J– e.g., isoleucine to threonine mutation at position 41 or a homologous residue in FIG4 (T>C mutation)– see, e.g., Lenk et al., PLoS Genetics.2011; 7:

e1002104; neuroblastoma (NB)– e.g., leucine to proline mutation at position 197 or a homologous residue in Caspase-9 (T>C mutation)– see, e.g., Kundu et al., 3 Biotech.2013, 3:225-234; von Willebrand disease (vWD)– e.g., cysteine to arginine mutation at position 509 or a homologous residue in the processed form of von Willebrand factor, or at position 1272 or a homologous residue in the unprocessed form of von Willebrand factor (T>C mutation)– see, e.g., Lavergne et al., Br. J. Haematol.1992, see also accession number P04275 in the UNIPROT database; 82: 66-72; myotonia congenital– e.g., cysteine to arginine mutation at position 277 or a homologous residue in the muscle chloride channel gene CLCN1 (T>C mutation)– see, e.g., Weinberger et al., The J. of Physiology. 2012; 590: 3449-3464; hereditary renal amyloidosis– e.g., stop codon to arginine mutation at position 78 or a homologous residue in the processed form of apolipoprotein AII or at position 101 or a homologous residue in the unprocessed form (T>C mutation)– see, e.g., Yazaki et al., Kidney Int. 2003; 64: 11-16; dilated cardiomyopathy (DCM)– e.g., tryptophan to Arginine mutation at position 148 or a homologous residue in the FOXD4 gene (T>C mutation), see, e.g., Minoretti et. al., Int. J. of Mol. Med.2007; 19: 369-372; hereditary lymphedema– e.g., histidine to arginine mutation at position 1035 or a homologous residue in VEGFR3 tyrosine kinase (A>G mutation), see, e.g., Irrthum et al., Am. J. Hum. Genet.2000; 67: 295-301; familial Alzheimer’s disease– e.g., isoleucine to valine mutation at position 143 or a homologous residue in presenilin1 (A>G mutation), see, e.g., Gallo et. al., J. Alzheimer’s disease.2011; 25: 425-431; Prion disease– e.g., methionine to valine mutation at position 129 or a homologous residue in prion protein (A>G mutation)– see, e.g., Lewis et. al., J. of General Virology.2006; 87: 2443-2449; chronic infantile neurologic cutaneous articular syndrome (CINCA)– e.g., Tyrosine to Cysteine mutation at position 570 or a homologous residue in cryopyrin (A>G mutation)– see, e.g., Fujisawa et. al. Blood.2007; 109: 2903-2911; and desmin-related myopathy (DRM)– e.g., arginine to glycine mutation at position 120 or a homologous residue in aB crystallin (A>G mutation)– see, e.g., Kumar et al., J. Biol. Chem.1999; 274: 24137-24141. The entire contents of all references and database entries is incorporated herein by reference.

Pharmaceutical compositions

[00412] Other aspects of the present disclosure relate to pharmaceutical compositions comprising any of the various components described herein (e.g., including, but not limited to, the napDNAbps, fusion proteins, guide RNAs, and complexes comprising fusion proteins and guide RNAs).

[00413] The term“pharmaceutical composition”, as used herein, refers to a composition formulated for pharmaceutical use. In some embodiments, the pharmaceutical composition further comprises a pharmaceutically acceptable carrier. In some embodiments, the pharmaceutical composition comprises additional agents (e.g. for specific delivery, increasing half-life, or other therapeutic compounds).

[00414] As used here, the term“pharmaceutically-acceptable carrier” means a pharmaceutically- acceptable material, composition or vehicle, such as a liquid or solid filler, diluent, excipient, manufacturing aid (e.g., lubricant, talc magnesium, calcium or zinc stearate, or steric acid), or solvent encapsulating material, involved in carrying or transporting the compound from one site (e.g., the delivery site) of the body, to another site (e.g., organ, tissue or portion of the body). A

pharmaceutically acceptable carrier is“acceptable” in the sense of being compatible with the other ingredients of the formulation and not injurious to the tissue of the subject (e.g., physiologically compatible, sterile, physiologic pH, etc.). Some examples of materials which can serve as pharmaceutically-acceptable carriers include: (1) sugars, such as lactose, glucose and sucrose; (2) starches, such as corn starch and potato starch; (3) cellulose, and its derivatives, such as sodium carboxymethyl cellulose, methylcellulose, ethyl cellulose, microcrystalline cellulose and cellulose acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) lubricating agents, such as magnesium stearate, sodium lauryl sulfate and talc; (8) excipients, such as cocoa butter and suppository waxes; (9) oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; (10) glycols, such as propylene glycol; (11) polyols, such as glycerin, sorbitol, mannitol and polyethylene glycol (PEG); (12) esters, such as ethyl oleate and ethyl laurate; (13) agar; (14) buffering agents, such as magnesium hydroxide and aluminum hydroxide; (15) alginic acid; (16) pyrogen-free water; (17) isotonic saline; (18) Ringer's solution; (19) ethyl alcohol; (20) pH buffered solutions; (21) polyesters, polycarbonates and/or polyanhydrides; (22) bulking agents, such as polypeptides and amino acids (23) serum component, such as serum albumin, HDL and LDL; (22) C2-C12 alcohols, such as ethanol; and (23) other non-toxic compatible substances employed in pharmaceutical formulations. Wetting agents, coloring agents, release agents, coating agents, sweetening agents, flavoring agents, perfuming agents, preservative and antioxidants can also be present in the formulation. The terms such as“excipient”,“carrier”,“pharmaceutically acceptable carrier” or the like are used interchangeably herein.

[00415] In some embodiments, the pharmaceutical composition is formulated for delivery to a subject, e.g., for gene editing. Suitable routes of administrating the pharmaceutical composition described herein include, without limitation: topical, subcutaneous, transdermal, intradermal, intralesional, intraarticular, intraperitoneal, intravesical, transmucosal, gingival, intradental, intracochlear, transtympanic, intraorgan, epidural, intrathecal, intramuscular, intravenous, intravascular, intraosseus, periocular, intratumoral, intracerebral, and intracerebroventricular administration.

[00416] In some embodiments, the pharmaceutical composition described herein is administered locally to a diseased site (e.g., tumor site). In some embodiments, the pharmaceutical composition described herein is administered to a subject by injection, by means of a catheter, by means of a suppository, or by means of an implant, the implant being of a porous, non-porous, or gelatinous material, including a membrane, such as a sialastic membrane, or a fiber.

[00417] In other embodiments, the pharmaceutical composition described herein is delivered in a controlled release system. In one embodiment, a pump may be used (see, e.g., Langer, 1990, Science 249:1527-1533; Sefton, 1989, CRC Crit. Ref. Biomed. Eng.14:201; Buchwald et al., 1980, Surgery 88:507; Saudek et al., 1989, N. Engl. J. Med.321:574). In another embodiment, polymeric materials can be used. (See, e.g., Medical Applications of Controlled Release (Langer and Wise eds., CRC Press, Boca Raton, Fla., 1974); Controlled Drug Bioavailability, Drug Product Design and

Performance (Smolen and Ball eds., Wiley, New York, 1984); Ranger and Peppas, 1983, Macromol. Sci. Rev. Macromol. Chem.23:61. See also Levy et al., 1985, Science 228:190; During et al., 1989, Ann. Neurol.25:351; Howard et al., 1989, J. Neurosurg.71:105.) Other controlled release systems are discussed, for example, in Langer, supra.

[00418] In some embodiments, the pharmaceutical composition is formulated in accordance with routine procedures as a composition adapted for intravenous or subcutaneous administration to a subject, e.g., a human. In some embodiments, pharmaceutical composition for administration by injection are solutions in sterile isotonic aqueous buffer. Where necessary, the pharmaceutical can also include a solubilizing agent and a local anesthetic such as lignocaine to ease pain at the site of the injection. Generally, the ingredients are supplied either separately or mixed together in unit dosage form, for example, as a dry lyophilized powder or water free concentrate in a hermetically sealed container such as an ampoule or sachette indicating the quantity of active agent. Where the pharmaceutical is to be administered by infusion, it can be dispensed with an infusion bottle containing sterile pharmaceutical grade water or saline. Where the pharmaceutical composition is administered by injection, an ampoule of sterile water for injection or saline can be provided so that the ingredients can be mixed prior to administration.

[00419] A pharmaceutical composition for systemic administration may be a liquid, e.g., sterile saline, lactated Ringer’s or Hank’s solution. In addition, the pharmaceutical composition can be in solid forms and re-dissolved or suspended immediately prior to use. Lyophilized forms are also contemplated.

[00420] The pharmaceutical composition can be contained within a lipid particle or vesicle, such as a liposome or microcrystal, which is also suitable for parenteral administration. The particles can be of any suitable structure, such as unilamellar or plurilamellar, so long as compositions are contained therein. Compounds can be entrapped in“stabilized plasmid-lipid particles” (SPLP) containing the fusogenic lipid dioleoylphosphatidylethanolamine (DOPE), low levels (5-10 mol%) of cationic lipid, and stabilized by a polyethyleneglycol (PEG) coating (Zhang Y. P. et al., Gene Ther.1999, 6:1438- 47). Positively charged lipids such as N-[1-(2,3-dioleoyloxi)propyl]-N,N,N-trimethyl- amoniummethylsulfate, or“DOTAP,” are particularly preferred for such particles and vesicles. The preparation of such lipid particles is well known. See, e.g., U.S. Patent Nos.4,880,635; 4,906,477; 4,911,928; 4,917,951; 4,920,016; and 4,921,757; each of which is incorporated herein by reference.

[00421] The pharmaceutical composition described herein may be administered or packaged as a unit dose, for example. The term“unit dose” when used in reference to a pharmaceutical composition of the present disclosure refers to physically discrete units suitable as unitary dosage for the subject, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect in association with the required diluent; i.e., carrier, or vehicle.

[00422] Further, the pharmaceutical composition can be provided as a pharmaceutical kit comprising (a) a container containing a compound of the invention in lyophilized form and (b) a second container containing a pharmaceutically acceptable diluent (e.g., sterile water) for injection. The

pharmaceutically acceptable diluent can be used for reconstitution or dilution of the lyophilized compound of the invention. Optionally associated with such container(s) can be a notice in the form prescribed by a governmental agency regulating the manufacture, use or sale of pharmaceuticals or biological products, which notice reflects approval by the agency of manufacture, use or sale for human administration.

[00423] In another aspect, an article of manufacture containing materials useful for the treatment of the diseases described above is included. In some embodiments, the article of manufacture comprises a container and a label. Suitable containers include, for example, bottles, vials, syringes, and test tubes. The containers may be formed from a variety of materials such as glass or plastic. In some embodiments, the container holds a composition that is effective for treating a disease described herein and may have a sterile access port. For example, the container may be an intravenous solution bag or a vial having a stopper pierceable by a hypodermic injection needle. The active agent in the composition is a compound of the invention. In some embodiments, the label on or associated with the container indicates that the composition is used for treating the disease of choice. The article of manufacture may further comprise a second container comprising a pharmaceutically-acceptable buffer, such as phosphate-buffered saline, Ringer's solution, or dextrose solution. It may further include other materials desirable from a commercial and user standpoint, including other buffers, diluents, filters, needles, syringes, and package inserts with instructions for use. Delivery methods

[00424] In some aspects, the invention provides methods comprising delivering one or more polynucleotides, such as or one or more vectors as described herein encoding one or more components described herein, one or more transcripts thereof, and/or one or proteins transcribed therefrom, to a host cell. In some aspects, the invention further provides cells produced by such methods, and organisms (such as animals, plants, or fungi) comprising or produced from such cells. In some embodiments, a base editor as described herein in combination with (and optionally complexed with) a guide sequence is delivered to a cell. Conventional viral and non-viral based gene transfer methods can be used to introduce nucleic acids in mammalian cells or target tissues. Such methods can be used to administer nucleic acids encoding components of a base editor to cells in culture, or in a host organism. Non-viral vector delivery systems include DNA plasmids, RNA (e.g. a transcript of a vector described herein), naked nucleic acid, and nucleic acid complexed with a delivery vehicle, such as a liposome. Viral vector delivery systems include DNA and RNA viruses, which have either episomal or integrated genomes after delivery to the cell. For a review of gene therapy procedures, see Anderson, Science 256:808-813 (1992); Nabel & Felgner, TIBTECH 11:211-217 (1993); Mitani & Caskey, TIBTECH 11:162-166 (1993); Dillon, TIBTECH 11:167-175 (1993); Miller, Nature 357:455-460 (1992); Van Brunt, Biotechnology 6(10):1149-1154 (1988); Vigne, Restorative Neurology and Neuroscience 8:35-36 (1995); Kremer & Perricaudet, British Medical Bulletin 51(1):31-44 (1995); Haddada et al., in Current Topics in Microbiology and Immunology Doerfler and Bihm (eds) (1995); and Yu et al., Gene Therapy 1:13-26 (1994).

[00425] Methods of non-viral delivery of nucleic acids include lipofection, nucleofection, microinjection, biolistics, virosomes, liposomes, immunoliposomes, polycation or lipid:nucleic acid conjugates, naked DNA, artificial virions, and agent-enhanced uptake of DNA. Lipofection is described in e.g., U.S. Pat. Nos.5,049,386, 4,946,787; and 4,897,355) and lipofection reagents are sold commercially (e.g., Transfectam™ and Lipofectin™). Cationic and neutral lipids that are suitable for efficient receptor-recognition lipofection of polynucleotides include those of Feigner, WO 91/17424; WO 91/16024. Delivery can be to cells (e.g. in vitro or ex vivo administration) or target tissues (e.g. in vivo administration). The preparation of lipid:nucleic acid complexes, including targeted liposomes such as immunolipid complexes, is well known to one of skill in the art (see, e.g., Crystal, Science 270:404-410 (1995); Blaese et al., Cancer Gene Ther.2:291-297 (1995); Behr et al., Bioconjugate Chem.5:382-389 (1994); Remy et al., Bioconjugate Chem.5:647-654 (1994); Gao et al., Gene Therapy 2:710-722 (1995); Ahmad et al., Cancer Res.52:4817-4820 (1992); U.S. Pat. Nos. 4,186,183, 4,217,344, 4,235,871, 4,261,975, 4,485,054, 4,501,728, 4,774,085, 4,837,028, and 4,946,787).

[00426] The use of RNA or DNA viral based systems for the delivery of nucleic acids take advantage of highly evolved processes for targeting a virus to specific cells in the body and trafficking the viral payload to the nucleus. Viral vectors can be administered directly to patients (in vivo) or they can be used to treat cells in vitro, and the modified cells may optionally be administered to patients (ex vivo). Conventional viral based systems could include retroviral, lentivirus, adenoviral, adeno-associated and herpes simplex virus vectors for gene transfer. Integration in the host genome is possible with the retrovirus, lentivirus, and adeno-associated virus gene transfer methods, often resulting in long term expression of the inserted transgene. Additionally, high transduction efficiencies have been observed in many different cell types and target tissues.

[00427] The tropism of a viruses can be altered by incorporating foreign envelope proteins, expanding the potential target population of target cells. Lentiviral vectors are retroviral vectors that are able to transduce or infect non-dividing cells and typically produce high viral titers. Selection of a retroviral gene transfer system would therefore depend on the target tissue. Retroviral vectors are comprised of cis-acting long terminal repeats with packaging capacity for up to 6-10 kb of foreign sequence. The minimum cis-acting LTRs are sufficient for replication and packaging of the vectors, which are then used to integrate the therapeutic gene into the target cell to provide permanent transgene expression. Widely used retroviral vectors include those based upon murine leukemia virus (MuLV), gibbon ape leukemia virus (GaLV), Simian Immuno deficiency virus (SIV), human immuno deficiency virus (HIV), and combinations thereof (see, e.g., Buchscher et al., J. Virol.66:2731-2739 (1992); Johann et al., J. Virol.66:1635-1640 (1992); Sommnerfelt et al., Virol.176:58-59 (1990); Wilson et al., J. Virol. 63:2374-2378 (1989); Miller et al., J. Virol.65:2220-2224 (1991); PCT/US94/05700). In applications where transient expression is preferred, adenoviral based systems may be used. Adenoviral based vectors are capable of very high transduction efficiency in many cell types and do not require cell division. With such vectors, high titer and levels of expression have been obtained. This vector can be produced in large quantities in a relatively simple system. Adeno-associated virus (“AAV”) vectors may also be used to transduce cells with target nucleic acids, e.g., in the in vitro production of nucleic acids and peptides, and for in vivo and ex vivo gene therapy procedures (see, e.g., West et al., Virology 160:38-47 (1987); U.S. Pat. No.4,797,368; WO 93/24641; Kotin, Human Gene Therapy 5:793-801 (1994); Muzyczka, J. Clin. Invest.94:1351 (1994). Construction of recombinant AAV vectors are described in a number of publications, including U.S. Pat. No.5,173,414; Tratschin et al., Mol. Cell. Biol.5:3251-3260 (1985); Tratschin, et al., Mol. Cell. Biol.4:2072-2081 (1984); Hermonat & Muzyczka, PNAS 81:6466-6470 (1984); and Samulski et al., J. Virol.63:03822-3828 (1989).

[00428] Packaging cells are typically used to form virus particles that are capable of infecting a host cell. Such cells include 293 cells, which package adenovirus, and y2 cells or PA317 cells, which package retrovirus. Viral vectors used in gene therapy are usually generated by producing a cell line that packages a nucleic acid vector into a viral particle. The vectors typically contain the minimal viral sequences required for packaging and subsequent integration into a host, other viral sequences being replaced by an expression cassette for the polynucleotide(s) to be expressed. The missing viral functions are typically supplied in trans by the packaging cell line. For example, AAV vectors used in gene therapy typically only possess ITR sequences from the AAV genome which are required for packaging and integration into the host genome. Viral DNA is packaged in a cell line, which contains a helper plasmid encoding the other AAV genes, namely rep and cap, but lacking ITR sequences. The cell line may also be infected with adenovirus as a helper. The helper virus promotes replication of the AAV vector and expression of AAV genes from the helper plasmid. The helper plasmid is not packaged in significant amounts due to a lack of ITR sequences. Contamination with adenovirus can be reduced by, e.g., heat treatment to which adenovirus is more sensitive than AAV. Additional methods for the delivery of nucleic acids to cells are known to those skilled in the art. See, for example, US20030087817, incorporated herein by reference.

Kits, vectors, cells

[00429] Some aspects of this disclosure provide kits comprising a nucleic acid construct, comprising (a) a nucleotide sequence encoding a Cas9 domain or a fusion protein comprising a Cas9 domain as provided herein; and (b) a heterologous promoter that drives expression of the sequence of (a). In some embodiments, the kit further comprises an expression construct encoding a guide RNA backbone, wherein the construct comprises a cloning site positioned to allow the cloning of a nucleic acid sequence identical or complementary to a target sequence into the guide RNA backbone.

[00430] Some aspects of this disclosure provide polynucleotides encoding a Cas9 domain or a fusion protein comprising a Cas9 domain as provided herein. Some aspects of this disclosure provide vectors comprising such polynucleotides. In some embodiments, the vector comprises a heterologous promoter driving expression of polynucleotide.

[00431] In one aspect, provided herein are methods comprising contacting a cell with a kit provided herein. In another aspect, provided herein are methods comprising contacting a cell with a vector provided herein. In some embodiments, the vector is transfected into the cell. In some embodiments, the vector is transfected into the cell using a suitable transfection reaction. Transfection reactions may be carried out, for example, using electroporation, heat shock, or a composition comprising a cationic lipid. Cationic lipids suitable for the transfection of nucleic acid molecules are provided in, for example, Patent Publication WO2015/035136, published March 12, 2015, entitled“Delivery System for Functional Nucleases”; the entire contents of which is incorporated by reference herein.

[00432] Some aspects of this disclosure provide cells comprising a Cas9 domain, a fusion protein, a nucleic acid molecule, and/or a vector as provided herein.

[00433] The description of exemplary embodiments of the reporter systems (e.g., GFP) herein is provided for illustration purposes only and not meant to be limiting. Additional reporter systems, e.g., variations of the exemplary systems described in detail above, are also embraced by this disclosure. REFERENCES

[00434] 1. Komor, A. C., Kim, Y. B., Packer, M. S., Zuris, J. A. & Liu, D. R. Programmable editing of a target base in genomic DNA without double-stranded DNA cleavage. Nature 533, 420–424 (2016).

[00435] 2. Nishida, K. et al. Targeted nucleotide editing using hybrid prokaryotic and vertebrate adaptive immune systems. Science 353, 1248 (2016).

[00436] 3. Gaudelli, N. M. et al. Programmable base editing of A.T to G.C in genomic DNA without DNA cleavage. Nature 551, 464–471 (2017).

[00437] 4. Rees, H. A. et al. Improving the DNA specificity and applicability of base editing through protein engineering and protein delivery. Nat. Commun.8, 15790 (2017).

[00438] 5. Kim, J.-S. Precision genome engineering through adenine and cytosine base editing. Nat. Plants 4, 148–151 (2018). EXAMPLES EXAMPLE 1

Identification of PAM sequences that SpCas9 and xCas9 have low activity

[00439] A key limitation to the use of CRISPR-Cas9 domains for genome editing and other applications is the requirement that a protospacer adjacent motif (PAM) be present at the target site. For the most commonly used Cas9 from Streptococcus pyogenes (SpCas9), this PAM requirement is NGG. No natural or engineered Cas9 variants shown to function efficiently in mammalian cells offer a PAM less restrictive than NGG. Phage-assisted continuous evolution (PACE) was used to evolve the wild type SpCas9 and an expanded PAM SpCas9 variant (xCas9) that can recognize a broad range of PAM sequences. The PAM compatibility of xCas9 is the broadest reported to date among Cas9s active in mammalian cells, and supports applications in human cells including targeted transcriptional activation, nuclease-mediated gene disruption, and both cytidine and adenine base editing.

[00440] Here, phage-assisted continuous evolution (PACE) is used for identification on PAMs that spCas9 and xCas9 have low activity. During PACE, host E. coli cells continuously dilute an evolving population of bacteriophages (selection phage, SP). Since dilution occurs faster than cell division but slower than phage replication, only the SP, and not the host cells, can accumulate mutations. Each SP carries a gene to be evolved instead of a phage gene (gene III) that is required for the production of infectious progeny phage. SP containing desired gene variants trigger host-cell gene III expression from the accessory plasmid (AP) and the production of infectious SP that propagate the desired variants. Phage encoding inactive variants do not generate infectious progeny and are rapidly diluted out of the culture vessel (FIG.1A). As phage replication can occur in as little as 10 minutes, PACE enables hundreds of generations of directed evolution to occur per week without researcher intervention.

[00441] To link Cas9 DNA recognition to phage propagation during PACE, a bacterial one-hybrid selection in which the SP encodes a catalytically dead SpCas9 (dCas9) fused to the w subunit of bacterial RNA polymerase was developed (FIG.1A). When this fusion binds an AP-encoded sgRNA and a PAM and protospacer upstream of gene III in the AP, RNA polymerase recruitment causes gene III expression and phage propagation (FIG.1B). A library of all 64 possible NNN PAM sequences at the target protospacer in the AP, so that SP encoding Cas9 variants with broader PAM compatibility would replicate in a larger fraction of host cells and thus experience a fitness advantage, was generated. After overnight propagation. As expected, xCas9 are less stringent on PAM requirement. Both SpCas9 or xCas9 exhibited low activity on NAA, NAC, and NAT PAMs (FIG.1C). The following experiments were designed to identify Cas9 variants that are able to bind to NAA, NAC, and NAT PAMs. EXAMPLE 2

Phage Assisted Non-continuous Evolution (PANCE) of Cas9 variants for expanded PAM compatibility

[00442] Phage-assisted non-continuous evolution (PANCE) system was used to further evolve SpCas9 and xCas9 for identification of Cas9 variants that can recognize non-NGG PAMs. In the PANCE system, the SP is iteratively passaged through serial dilution in host cells in order to evolve SpCas9 and/or xCas9 proteins that bind to all possible The PANCE system preferentially replicates Cas9 variants that bind a greater variety of PAM sequences, similar to PACE, but with lower stringency since there is no outflow of phage. Although lower in stringency, the PANCE system allows for higher throughput, enabling evolution towards multiple targets (e.g., NAA, NAC, NAT PAMS) simultaneously.

[00443] In this experiment, SPs were iteratively passaged through serial dilution in host cells to evolve either SpCas9 or xCas9 proteins capable of binding to all 16 NAN PAM target sequences. In PANCE, E. coli host cells transformed with an AP and mutagenesis plasmid (MP) or dilution plasmid (DP) are plated in individual wells of a multi-well plate and grown to log phase. Selection phages, are then introduced and mutagenesis is induced with arabinose or aTc. The SPs are then grown for at least 6 additional hours, before being collected and used to infect the next multi-well plate of E. coli host cells that have grown to log phase (FIG.2A). Each one of these infection-incubation-collection cycles is referred to as a“passage”.

[00444] Increased recognition of non-NGG PAMs were observed in both SpCas9 and xCas9 as they were evolved through more passages in PANCE. FIG.2B shows evolving SpCas9 and xCas9’s ability to recognize all 64 PAMs for passage 2, passage 12 and passage 16. After performing 19 rounds of selection in PANCE and sequencing the surviving phage pools (FIG.36), mutations largely differing according to the third base of the NAN PAM targeted for evolution were observed. For example, variants selected on NAA enriched for Gly, Ile, or Lys at position 1333, while those selected for NAT enriched for Gln or Leu at position 1335. Finally, variants evolved to bind NAC enriched simultaneously for Gln at position 1335 and Asn at position 1337.

[00445] The clones of mutated SpCas9 and xCas9 variants that were able to recognize NAA PAMs were isolated and sequenced for identification of mutations in Cas9. FIG.3A shows mutations in SpCas9 at passage 12 that can recognize CAA, GAT, ATG, or AGC PAMs. FIG.4A shows mutations in SpCas9 at passage 19 that can recognize ATG, CAA, or GAA PAMs. Further, the wild type SpCas9 clones, e.g., CAA-3, GAT-2, ATG-2, ATG-3, or AGC-3 in passage 12 were tested using the luciferase assay described above for their ability to recognize all 64 PAMs, as shown in FIG. 3B. Similarly, the wild type SpCas9 clones, e.g., CAA-1, CAA-2, GAA-1, GAA-2, GAC-5, GAT-1, GAT-3, AGC-1, AGC-3, AGC-6. ATG-3, or ATG-6 in passage 19 were tested using the luciferase assay described above for their ability to recognize all 64 PAMs, as shown in FIG.4B.

[00446] Similarly, FIG.5A shows mutations in xCas9 at passage 12 that can recognize TAT, GTA, or CAC PAMs, and FIG.6A shows mutations in xCas9 at passage 19 that can recognize AAA, GCC, or TAA PAMs. Further, xCas9 mutant clones, e.g., TAT-1, TAT-3, GTA-1, GTA-3, or CAC-2 in passage 12 were tested using the luciferase assay described above for their ability to recognize all 64 PAMs, as shown in FIG.5B. Similarly, xCas9 mutant clones, e.g., AAA-1, TAA-2, TAA-5, TAT-5, CAC-5, CAC-6, GTA-2, GTA-7, GCC-2, GCC-5, or GCC-8 in passage 18 were tested using the luciferase assay described above for their ability to recognize all 64 PAMs, as shown in FIG.6B.

[00447] To test if mutations evolved during PANCE in bacteria are compatible with xCas9 function in mammalian cells, SpCas9 and xCas9 variants were characterized for their activity and PAM compatibility in human cells in two contexts: adenine base editing and genomic DNA cutting.

Additionally, to further characterize genomic DNA cleavage in human cells by xCas9 variants, we targeted endogenous genomic sites in HEK293T cells and measured indel formation by high- throughput sequencing (HTS).

[00448] To evaluate C•G-to-T•A base editing activity of xCas9 variants, SpCas9 was substituted with xCas93.7 and 3.6 in the third-generation (BE3) base editor architecture. Both xCas9–BE3s were transfected into mammalian cells to compare editing efficiency. The xCas9-BE3 protein

demonstrated base editing activity only on CGT and CGG PAMs, whereas the ATG2-BE3 protein demonstrated base editing activity on CAG and ATG PAMs, the CAA3-BE3 protein demonstrated base editing activity on CGG PAMs, and the TAT1-BE3 protein demonstrated base editing activity on CAT PAMs (FIG.7).

[00449] The xCas9 protein produced indels in CAG, ATG, CAT, CGT, and CGG PAMs, whereas the ATG2 protein produced indels in CAG and CGG PAMs, the CAA3 protein produced indels in CAT and CGG PAMs, and the TAT1 protein produced indels in CAT PAMs (FIG.7).

[00450] Thus, the PANCE evolved spCas9 variants have some activity in vitro on non-NGG PAMs.

[00451] Additionally, the xCas9-passage 12-TAT1 (N6) variant was subjected to further PANCE evolution. A comparison of xCas9-passage 12-TAT1 to SpCas9 in various amino acid residues was shown in FIG.9A. The clones resulting from further PANCE evolution of the xCas9-passage 12- TAT1 (N6) variant are shown in FIGs.10-11. FIG.12 shows evolving’s xCas9-passage 12-TAT1 variant’s ability to recognize all 64 PAMs for passage 2, passage 12 and passage 16.

EXAMPLE 3

Selection improvement allows the evolution of NAA PAM binding activity

[00452] Despite enriching for multiple consensus mutations in the PAM-interacting domain (PID), (D1135N/E1219V/Q1221H/H1264Y/A1320V/R1333K), the NAA-targeted PANCE-evolved mutants exhibited low activity when subcloned into C to T base editors (CBEs) and tested for base conversion on sites containing NAA PAMs in mammalian cells (FIGs.7, 37C). One possible explanation is that evolving increased binding activity might require increased selection stringency, and three strategies were implemented to accomplish this.

[00453] First, two variants evolved to bind a CAA PAM in the initial PANCE assay were selected and subjected to PACE using a dual-AP system. Here, each AP provides one half of slit- intein pIII under control of an orthogonal Cas91-hybrid circuit, requiring w-dCas9 to successfully bind two distinct protospacer-PAM motifs to produce full-length pIII (FIGs.13A, 13B, 37A). These experiments led to the acquisition of a few additional consensus mutations (FIGs.14A, 37B). This in turn led to improvements in CBE on sites (FIGs.14B, 37C) and increased percentages of indels in mammalian cells (FIG.14C).

[00454] Next, the total amount of Cas9 present in the selection was limited by using a split- intein to divide w-dCas9 into two halves and encoding only the C-terminal half (which contains the PID) on the SP. Production of large amounts of w-dCas9 by the SP might lead to saturation of binding to protospacer-PAM sites AP despite the presence of a non-optimal PAM (FIG.15A).

Indeed, using higher concentrations of SpCas9 in in vitro PAM depletion assays can lead to depletion of non-canonical PAM sequences (REF). Here, residues 574-1368 of Cas9 fused to NpuC (dCas9 _C ) reside on the phage, while w-dCas9 (1-573) fused to NpuN (w-dCas9 _N ) is provided on a

complimentary plasmid (CP) (FIGs.15B, 37A). This strategy allows the total amount of full-length SpCas9 produced in the host cells in PACE to be user-defined on the CP.

[00455] The consensus mutations obtained from the dual-AP selection were subcloned into a split-intein w-dCas9 format. However, several mutations (T10A/I322V/S409I,E427G) had accumulated in the 1-573 region over the course of the previous selection. These mutations were incorporated into w-dCas9 _N and investigated their effect on Cas9 DNA binding in overnight phage propagation assays using an evolved dCas9 _C phage clone (P4.72.5). High phage propagation was observed on host cells containing a CP encoding w-dCas9 _N (T10A/I322V/S409I/E427G), suggesting that the mutations might have a beneficial effect on Cas9 binding. Therefore, these four mutations were incorporated into w-dCas9 _N for all future evolutions (hereon referred to as w-dCas9 _N-mut ).

[ _00456] Thus, the evolved dCas9 _{C was subjected} to two subsequent evolutions using host _cells encoding a medium-copy AP containing an AAA PAM and low-copy CPs providing w-dCas9 _N-mut from increasingly weak constitutive promoters. These rounds lead to the _{accumulation of} additional mutations in the PID, including D1180G, which was present in several sequenced clones (FIGs.16A, 37B). The Cas9s evolved through this split-intein method exhibited a large increase in mammalian cell base editing activity, with more than double the activity of our previous variants on most NAA sites tested (FIGs.17, 37C). Additionally, the Cas9s evolved through this split-intein method exhibited a large increase in percentage of indels in most NAA PAMs tested (FIG.18).

[00457] Finally, to further increase selection stringency, gVI, whose protein product pVI is essential for phage propagation, was removed from the phage genome for use as an orthogonal selection marker for phage propagation on a second AP (FIGs.27A). Both previously described selection principles were employed, requiring a split-intein w-dCas9 to bind two distinct protospacers on APs providing both gIII and gVI (FIG.37A). Thus, three dCas9 _C clones from pervious evolutions (P13.3.3, P10.5.192.7, P10.6.192.1) were subjected to this highest-stringency selection in PACE, resulting in additional mutations in the PID-notably R1114G and L1318S, which both converged to a high degree (FIG.37B).

[00458] Unfortunately, these variants proved to be inactive in mammalian cell CBE experiments (FIG.37C). The large numbers of mutations present in these highly evolved variants, especially those outside the PID, might prove deleterious to expression and/or nuclease activity. To address this, DNA shuffling was performed of the C-terminal portion (residues 574-1368) of the pool of variants from this final evolution with that of wild-type Cas9 and re-subjected the resulting library to the most stringent binding selection. This led to the isolation of several clones that exhibited improved CBE activity at both NAA and NGA sites in mammalian cells, most notably clone P16s.4-5 (R1114G/D1135N/V1139A/D1180G/E1219V/Q1221H/A1320V/R1333K) (FIG.37B), which exhibited the highest levels of activity across all sites tested amongst the variants (FIG.37C).

EXAMPLE 4

Evolution of Cas9 variants that recognize NAC or NAT PAM sequences

[00459] The strategy evolved in Example III was employed in evolving toward NAT and NAC PAMs in SpCas9 and xCas9 proteins to minimize the accumulation of potentially deleterious bystander mutations. To ensure the variants retained nuclease activity, the dCas9 from the SP pool was evolved to bind either a TAT or CAC PAM in PANCE to a nuclease-active form and passed the resulting library through a modified version of a previously reported bacterial DNA cleavage selection (data not shown). Here, Cas9 variants are challenged for their ability to bind to and cleave a protospacer-PAM sequence on a high-copy plasmid that also encodes a conditionally toxic gene (sacB). The surviving cells should then encode Cas9 variants with mutations that confer binding to a specific PAM and are compatible with nuclease activity.

[00460] From these experiments, two clones were isolated that exhibited DNA cleavage activity on a selection plasmid containing a TAT PAM with PID consensus mutations of

D1135N/E1219V/Q1221H/P1321S/R1335L, and one clone that cleaved a selection plasmid with a CAC PAM with PID mutations N1135D/E1219V/D1332N/R1335Q/T1337N (FIGs.37D, 37E). These nuclease-active TAT and CAC variants were then converted into split-intein w–dCas9 format and evolved in PACE using host cells encoding APs with either NAT (AAT or TAT) or NAC (AAC, TAC, or CAC) PAMs, respectively. These experiments resulted in the enrichment of several additional PID mutations, including R1114G, which arose independently in all three PAM trajectories (NAA, NAT, and NAC) (FIGs.37D, 37E), suggesting that this mutation may be generally beneficial for modifying PAM recognition by the PID.

[00461] Next, gVI was removed from the genome of these evolved SP pools, which were subjected to additional selection in PACE using a dual-AP system containing two distinct protospacers and either an AAT or TAC PAM driving gIII/gVI expression. A Y1131C mutation was enriched in the SP pool evolved on AAT (FIG.37E); however, variants carrying this mutation were inactive in mammalian cell BE experiments (Supplementary Figure XX). Because no additional functional mutations in the PID were observed, the most active NAT PAM-targeting variant was selected from the split-intein w–dCas9 evolution (clone P12.3.b9-8) to move forward with. This variant contained the PID mutations R1114G/D1135N/D1180G/G1218S/E1219V/Q1221H/P1249S/E1253K/

P1321S/D1332G/R1335L (FIG.37E).

[00462] Several additional mutations were also enriched in the SP pool selected for binding to a TAC PAM in the split-intein w-dCas9/dual protospacer PACE. The C-terminal portion (residues 574-1368) of this pool was shuffled with that of wild-type Cas9 and re-challenged the resulting library with our most stringent binding selection. From the surviving SP pool, clone P17s.1.7-4 with the PID mutations R1114G/D1135N/E1219V/D1332N/R1335Q/T1337N/S1338T/H1249R was isolated from the surviving pool (FIG.37C).

EXAMPLE 5

Mutations outside of the PID

[00463] Structural studies of the SpCas9 suggest that residues in the PID mediate PAM specificity (REF). Indeed, most of the previous efforts to engineer or evolve SpCas9 to accept alternative PAMs have focused on modulating this region of the protein. However, because PANCE and PACE experiments involved mutagenesis of either the entire SpCas9 sequence or residues 574- 1368 (in the case of split-intein w–dCas9), there was an enrichment of a number of mutations outside of the PID. Because many of these mutations fell within the RuvC or HNH nuclease domains, some may negatively impact Cas9 nuclease activity. However, other mutations in the helical domain consistently enriched across several independent evolving populations, suggesting that they may confer a beneficial effect on Cas9 DNA binding/unwinding. [00464] Therefore, to minimize the deleterious effects from bystander mutation accumulation in the nuclease domains but also to preserve beneficial mutations in the helical domain, the evolved PIDs from Example 4 were transferred onto a fixed N-terminal sequence that included the mutations T10A/I322V/S409I/E427G shown to improve phage propagation in the split-intein w– dCas9 selection, as well as R654L/R753G, which consistently enriched across multiple independently evolving SP pools. The addition of these mutations to CBEs containing the PIDs of NAA variant P16.4-5 and NAC variant P17.1.7-4 improved CBE activity in mammalian cells across several sites when compared to just the PID mutations alone (data not shown). A smaller effect was observed for NAT variant P12.3.b9-8, but because there did not appear to be a decrease in overall CBE activity (data not shown), there N-terminal mutations were incorporated into all three final variants, from hereon referred to as NRRH, NRCH, and NRTH, which are derived from clones P16.4-5, P17.1.7-4, and P12.3.b9-8, respectively.

EXAMPLE 6

Characterization of PAM specificity through bacterial depletion

[00465] To better characterize the PAM specificities of the evolved variants, bacterial PAM depletion was performed using a library consisting of 4Ns following the protospacer (FIGs.19A- 19C). For comparison, depletion experiments were also performed with wild-type Cas9 that acts on an NGG PAM sequence (SpCas9-NG) in parallel. Cells were plated after 1 or 3 h or overnight expression of the SpCas9 variant from an inducible promoter to better resolve any kinetic differences in PAM sequence preference. As expected, depletion scores of any given PAM increased with longer induction times (data not shown), with the shortest induction times resulting in the most noticeable sequence preferences (data not shown).

[00466] For example, at 1 hour (h) induction, NRRH exhibited a strong preference for C at the 4 ^th PAM position, a mixed preference for G/A at positions 2 and 3 and a moderate preference for G at position 1 (FIGs.20, 38A). However, longer induction times resulted in more relaxed specificity at all positions. Similarly, NRCH showed a strong preference for G at position 2 and a moderate preference for pyrimidines at position 4 (FIG.38A) at 1 h induction, but only a mixed enrichment for G/A at position 2 was observable at longer induction times (FIG.38A). Finally, at 1 h induction, NRTH enriched strongly for G and T at positions 2 and 3, respectively (FIG.38A), but by 3 h we observed a shift in the nucleotide preference at position 2 to a mix of G and A, suggesting that this variant recognizes and cleaves NAT PAMs more slowly when compared to NGT PAMs. Additionally, this suggests that NRTH may preferentially recognize NRT over NGG PAMs.

[00467] Interestingly, SpCas9-NG displayed a moderate preference for G at the 3 ^rd and 4 ^th PAM position at short induction times. This is consistent with SpCas9-NG’s T1337R mutation, which is also found in SpCas9 VRER and VRQR [REF] and is the cause for the increased specificity for G at the 4th PAM position of these variants. Similar to the evolved Cas9 variants, SpCas9-NG’s PAM sequence requirements also became more relaxed with longer induction times (data not shown).

[00468] Further, the P11 clone, which also possesses the P4.2.72.4 spCas9 mutations, was evolved using split-intein Cas9 mutants on AAA PAM bacterial depletion to generate clones with new mutations (FIG.21). The ability of the newly P11-SacB-1 and P11-SacB-2 clones to perform base- editing and generate indels was evaluated in vitro in HEK293T cells (FIGs.22-23). Both the P11- SacB-1 and P11-SacB-2 clones had higher base editing activity and a greater percentage of indels generated compared to xCas9 proteins (FIGs.22-23).

[00469] Similarly, the P12 clone was evolved using split-intein Cas9 mutants on AAT or TAT PAM bacterial depletion to generate clones with new mutations (FIGs.24A-24B). The ability of these newly-generated P12.3.b9-8 and P12.3.b10 clones to perform base-editing and generate indels was evaluated in vitro in HEK293T cells (FIGs.25A, 25B, 26A, 26B).

EXAMPLE 7

Survival-based selection for isolating nuclease-active Cas9 variants [00470] A survival-based selection method for isolating nuclease-active SpCas9 clones was generated (FIG.28). The SacB gene produces a toxic protein, and clones that survive this selection will have active nuclease that can cut the SacB gene. The original TAT clone was generated from PANCE on a TAT PAM, but lacked nuclease activity. This TAT cloned was subcloned from a pool of N4.TAT selection phage (SP) into a Cas9 plasmid and selection was performed for variants that cut a SacB selection plasmid with a TAT PAM. Two additional TAT clones, SacB-TAT-1 and SacB-TAT-2, were isolated (FIGs.29A, 29B).

[00471] These SacB-TAT-1 and SacB-TAT-2 clones were evaluated for their ability to perform base editing and generating indels in vitro in HEK293T cells (FIGs.30A, 30B, 31). The SacB-TAT-1 and SacB-TAT-2 clones both possessed higher base editing activity on GAT, CAT, and GAAP AMs compared with xCas9 (FIG.30A), as well as higher indel generation on GAT and TAT PAMs compared with xCas9 and spCas9 (FIGs.30B, 31).

EXAMPLE 8

Evolved Cas9 to generate indels at endogenous human genomic loci

[00472] The activity of the evolved SpCas9 and xCas9 variant proteins was assessed in HEK293T cells through indel formation at endogenous target sites spanning all 64 NANN PAMs. For comparison, the activity of the SpCas9 wild-type (SpCas9-NG) protein was tested at these sites in parallel. Generally, each of the variants displayed the highest indel formation activity on target sites containing a PAM it was evolved to recognize, with NRRH and NRTH showing an average of 23.0±7.8% and 22.9±7.2% indel formation on target sites containing NAAN and NATN PAMs, respectively. Sites containing NACN PAMs were edited at slightly lower efficiencies, with NRCH averaging 18.0±5.9% indel formation. Additionally, NRRH displayed 20% average indel formation on sites containing a NAG PAM, even though it had not been evolved to bind this PAM sequence (FIG. 38B). [00473] Interestingly, indel formation was observed with SpCas9-NG at a number of NANN sites. Although its average indel formation across these sites was lower than the evolved variants, SpCas9-NG displayed activity at sites with NANG PAMs (12.2±3.0%, 11.9±5.2%, 21.2±6.2%, and 18.3±4.4% average indel formation for NAAG, NACG, NATG, and NAGG, respectively) (FIG.38B). In contrast, the evolved variants showed the lowest average activity at sites with PAM sequences with a G at position 4, and the highest at sites with a non-G (H) at this position (27.3±8.6%, 23.7±6.8, 26.9±8.1%, and 26.8±7.6% average indel formation for NRRH, NRCH, NRTH, and NRRH on NAAH, NACH, NATH, and NAGH PAMs, respectively) (FIGs.38B, 38C). These results are consistent with the sequence preferences predicted by the bacterial PAM depletion experiments, and suggest that the variants and SpCas9-NG exhibit orthogonal PAM specificities.

[00474] The indel formation activity of evolved variants and SpCas9-NG were tested on a number of endogenous target sites containing NGN PAMs, with SpCas9-NG, NRCH, and NRTH performing best on NGA, NGC, and NGT PAMs, respectively, with 41.1±10.7%, 42.4±4.4%, and 67.7±6.8% average indel formation (data not shown). Similar to above, a preference for H at position 4 of the PAM by our variants was observed in these experiments.

[00475] Thus, increasing the DNA targeting capabilities of SpCas9 and xCas9 variants towards NRN PAMs could also greatly increase the proportion of genomic off-target sequences accessible by these Cas9 variants.

EXAMPLE 9

Evolved Cas9s are compatible with base editing technology

[00476] Next, the ability of evolved Cas9 variant proteins to support base editing was determined. C to T base editors (CBEs) were generated by incorporating the evolved Cas9 variants into BE4max (REF) in place of wt-Cas9. The activity of these CBEs was analyzed at the same 64 endogenous examined above for indel formation. As before, each of the three variants showed the highest average activity on sites containing the PAM it was evolved to recognize. BE4max-NRRH and BE4max-NRTH performed best on NAAN and NATN PAMs, with an average of 11.7±3.7% and 17.3±4.0% C•G to T•A conversion, respectively. CBE activity on NACN PAMs was slightly less efficient, with BE4max-NRCH enabling the highest editing activity at these sites at an average of 10.8±3.0% base conversion. Both BE4max-NRRH and BE4max-NG edit NAGN sites similarly, at 11.4±3.6 and 11.6±4.8% average base conversion (FIG.39A).

[00477] Improved base editing activity was again observed on sites with NANH PAMS, where C•G to T•A conversion at NAAH, NACH, NATH, and NAGH sites increasing to 14.4±4.1%, 13.0±2.6%, 21.0±4.2%, and 14.5±4.0 for BE4max-NRRH, -NRCH, -NRTH, and -NRRH, respectively (FIGs.39A, 39B). BE4max-NG performs well at sites containing NANG PAMs, with 13.6±4.4% average editing (FIG.39A). These editors also function on sites with NGN PAMs (data not shown). As expected, the CBE activity across all 64 sites is much more variable than that of indel formation, since there are increased requirements for efficient base editing such as sequence context and position of the C within the window. Finally, the Cas9 variants are also compatible with A to T base editors, exhibiting similar performance on a subset of sites containing NAN and NGN PAMs when substituted in place of wt-Cas9 in ABEmax (FIG.39C).

EXAMPLE 10

Characterization of evolved Cas9s and SpCas9-NG using a mammalian library for base editing activity

[00478] Finally, to thoroughly profile the PAM preferences of these variants, the base editing efficiencies of the three evolved variants, SpCas9-NG, and wt-Cas9 were evaluated on a library of 11,776 unique sequences in mammalian cells. This library was designed using 46 distinct protospacers derived from sequences found in the human genome, each with different sequence contexts surrounding a fixed C in the 4th position. Each protospacer is adjacent to a PAM sequence of 4Ns, and is additionally flanked with designated primer binding sites for amplification for high- throughput sequencing (HTS) analysis (FIG.40B). [00479] Characterization of the evolved variants in this library format recapitulated the same preferences observed with both bacterial PAM depletion and base editing on endogenous mammalian genomic sites. For instance, our evolved variants exhibited the highest editing activity on the third base towards which it was evolved (FIG.40E) or when a non-G was at the 4th position of the PAM, performing best when a pyrimidine was at this position (FIG.40F). Additionally, our evolved variants, in particular NRRH, performed best when a G or C was present at position 1 of the PAM, whereas wt-Cas9 exhibited only slight preference for G at this position (data not shown).

[00480] The U6 promoter, commonly used to express sgRNAs in mammalian cells, initiates transcription with a 5’ G. If a G is not natively present at the 5’ end of the protospacer, guide sequences are typically either extended to the next native G or transcribed with a mismatched G at position 21 of the guide sequence. However, high-fidelity (HF) Cas9s, which are less tolerant of mismatches between the protospacer and sgRNA, exhibit decreased efficiency when using a 21 nucleotide (nt) with a mismatched 5’ G [REF]. Because PACE has previously led to Cas9s with HF properties, including sgRNA mismatch intolerance [REF], we sought to determine if our new variants shared the same characteristics.

[00481] The average base editing activity of the evolved variants was evaluated across all sites containing either a 20 nt protospacer with a matched 5’ G, a 21 nt protospacer with a matched 5’ G, or a 21 nt protospacer with a mismatched 5’G. Both the evolved variants and wt-Cas9 showed the highest base editing activity with a 20 nt protospacer and a matched 5’ G. When examining all NNNN PAMs, both the variants and wt-Cas9 showed a significant decrease in base editing efficiency when the protospacer was increased to 21 nt, regardless if the 5’ G was matched with the target sequence (FIG.40C). The magnitude of this decrease was greater for the evolved variants when compared to wt-Cas9. Interestingly, the deleterious effect of using a 21 nt protospacer on editing efficiency is ameliorated when targeting sites with a NGNN PAM (data not shown), and almost completely absent when targeting sites with a NGGN PAM (FIG.40D). This is especially true for wt-Cas9, which shows no significantly decreased base editing activity on sites with a 21 nt protospacer when the PAM is NGG.

EXAMPLE 11

Evolved Cas9s correct disease-associated SNPs by accessing non-G PAMs

[00482] To demonstrate the utility of the evolved variants in a disease-relevant context, the Glu to Val point mutation at position 6 of the sickle-hemoglobin (HbS) variant of b-globin, which is causative of red blood cell sickling in sickle-cell anemia, was targeted [REF]. The HbS mutation arises from a GAG to GTG codon change, which cannot be fully reverted through current base editing technologies. However, this SNP can be partially corrected with ABE to a GCG (Ala) through A·T to G·C conversion on the opposite strand. This genotype, known as the Makassar mutation, has been shown to result in phenotypically normal hemoglobin.

[00483] Unfortunately, the only NGG or NGN PAMs available at this site place the target A at either position 2 or 9, respectively, which fall outside the optimal editing window for ABE.

However, two alternative target protospacer sequences that fall adjacent to a CAT or CAC PAM place the target A at either position 4 or 7, respectively, with an off-target A present at either position 6 or 9 leading to a silent CCT to CCC (Pro to Pro) mutation. Thus, the ability of the evolved variants, along with SpCas9-NG, to convert the sickle-cell SNP to the Makassar mutation using these alternative sites with non-G PAMs was evaluated.

[00484] In experiments using HEK293T cells engineered with a GAG to GTG mutation at codon 6 of b-globin, while the evolved variants supported considerable A to G conversion at both sites, SpCas9-NG edited efficiently only using the protospacer sequence containing a CAT PAM. This is perhaps due to the presence of a G at the 4th position of this PAM sequence (FIGs.41B, 41C), which appears to improve SpCas9-NG’s recognition of NAN PAMs (see above). Unfortunately, editing using the CAT PAM protospacer occurred primarily at the off-target base (position 6), with the target A (position 4) showing less than 10% conversion across all editors (FIG.41C). Base conversion using the CAC PAM protospacer, however, was much more efficient. As expected, ABEmax-NRCH showed the highest editing activity, with 40.6±6.5% base conversion at the target A (position 7) and 13.0±5.6% at the off-target A (position 9).

[00485] ABEmax-NRRH and -NRTH were also able to achieve 28.9±7.4% and 14.1±4.8% conversion, respectively. The high activity of all three evolved variants at this site likely stems from the presence of a C at the 4th position of the CAC PAM sequence. In comparison, ABEmax-NG showed negligible (1.0±0.8%) base conversion activity at this site (FIG.41B). Collectively, these results suggest that both the evolved variants and SpCas9-NG have the potential to edit disease relevant SNPs using non-G PAMs, and furthermore highlight the utility of targeting a SNP using multiple protospacer/PAM sequences.

[00486] Together with SpCas9-NG, the evolved variants NRRH, NRCH, and NRTH should expand the targeting scope of SpCas9 to sites with NR PAMs, increasing the number of pathogenic SNPs correctable by either CBE or ABE. Based on analysis of the ClinVar database, 95.0% of pathogenic SNPs correctable through a C·G to T·A conversion and 94.7% of pathogenic SNPs correctable through an A·T to G·C conversion can be targeting using an NR PAM. Additionally, expansion to NR PAMs increases the number of possible protospacers available for targeting a given SNP for correction with base editors: on average, there are XX protospacers per disease SNP targetable with CBE and XX protospacers for those targetable with ABE with NR PAMs, compared to XX targetable with CBE and XX targetable with ABE, respectively, when using NG PAMs.

EXAMPLE 12

[00487] Characterizing Mutants that Work on NRRH, NRCH, and NRTH PAMs

[00488] SpCas9 mutant proteins were identified that work best on NRRH, NRCH, and NRTH PAMs. The SpCas9 mutant protein that works best on NARH (“es” variant), has an amino acid sequence as presented in SEQ ID NO: 22 (underligned residues are mutated from SpCas9) MDKKYSIGLDIGTNSVGWAVITDEYKVPSKKFKVLGNTDRHSIKKNLIGALLFDSGETAE ATRLKRTA RRRYTRRKNRICYLQEIFSNEMAKVDDSFFHRLEESFLVEEDKKHERHPIFGNIVDEVAY HEKYPTIY

[00489] The SpCas9 mutant protein that works best on NRCH (“fn” variant), has an amino acid sequence as presented in SEQ ID NO: 23 (underligned residues are mutated from SpCas9)

[00490] The SpCas9 mutant protein that works best on NRTH (“ax” variant), has an amino acid

[00491] The base-editing activity of the ax, es, fn, and SpCas9 (“NG”) proteins was characterized in vitro in HEK293T cells on NAA, NAC, NAT, and NAG PAMs (FIGs.33A-33D; 34A-34B). The es protein had increased activity on CAAA, CAAC, AAAT, and GAAC PAMs, the fn protein had increased activity on AACC, AACT, TACT, TACC, CACT, and CACC PAMs, the ax protein had increased activity on AATA, TATT, TATA, TATC, CATA, CATT, CATC, GATA, GATT, and GATC PAMS compared with other SpCas9 proteins (FIGs.33A-33C; 34A-34B).

[00492] The A to G base editing activity of es and fn SpCas9 proteins were also characterized in vitro in HEK293T cells on NAA, NGA, NAC, and NGC PAMs (FIGs.35A-35C). The es, fn, or wild-type SpCas9 proteins were incorporated into the ABEMAX A to G gene editing fusion protein. The es protein had increased base-editing activity on AAAT, CAAC, GAAC, AACC, TACT, TACC, CACT, CACC, AGCC, AAGA, and AAGC PAMs compared with NG SpCas9 protein (FIGs.35A, 35B). The fn protein had increased base-editing activity on GGGT and TGGC compared with NG SpCas9 protein (FIG.35C). EXAMPLE 13

[00493] Continuous evolution of SpCas9 variants compatible with non-G PAMs

[00494] Streptococcus pyogenes Cas9 (SpCas9) is a widely used genome editing tool, but can only access a small fraction of DNA sites due to its requirement for an NGG protospaceradjacent motf (PAM). This limits SpCas9’s utility for precision genome editing

applications such as base editing (Rees and Liu, 2018), homology-directed repair (Paquet et al., 2016), and predictable template-free end-joining repair (Shen et al., 2018). While

SpCas9 variants with alternative PAM requirements have been reported, their targeting scope remains primarily restricted to PAMs containing G. Here, we report the laboratory

evolution of three new SpCas9 variants collectively capable of recognizing NRNH PAMs

(where R = A or G and H = A, C, or T) using an improved phage-assisted continuous evolution (PACE) selection for DNA binding. We show that these variants recognize

NAAH, NACH, NATH, and NAGH PAMs to effect indel formation, cytosine base editing, and adenine base editing using a panel of 64 endogenous human genome target sites

containing all NANN PAMs. Additionally, we profile the editing efficiencies of our evolved SpCas9s and the previously-reported SpCas9-NG as base editors on a 11,776-member genomically integrated protospacer/sgRNA pair library spanning all NNNN PAMs in HEK293T cells to provide an exhaustive characterization of their PAM preferences in a human cell setting. Finally, we demonstrate the ability of our variants to enable A•T-to- G•C base editing of the founder sickle-cell anemia mutation of b-globin using a previously inaccessible CAC PAM. Together with previously reported SpCas9 mutants, these newly evolved variants expand the targeting scope of SpCas9 to include a majority of NR PAM sequences, greatly increasing the fraction of genomes accessible to Cas9- mediated genome editing.

[00495] The CRISPR-Cas9 system, originally evolved as a mechanism for adaptive immunity in bacteria, has in recent years transformed the life sciences by enabling a wide range of techniques for targeted genome manipulation including gene disruption, homologydirected repair, gene regulation, and base editing (Komor et al., 2017). The applicability of these techniques is limited by the requirement of Cas9 for a protospacer-adjacent motif (PAM) in order to bind a DNA sequence. For example, wild-type Streptococcus pyogenes Cas9 (SpCas9), the most widely-used and well- characterized Cas9 homolog (Komor et al., 2017), recognizes an NGG PAM immediately 3’ of the target DNA sequence, and with rare exception will not efficiently engage DNA sequences lacking an NGG PAM (Jinek et al., 2012). To address this limitation and expand the range of targetable genomic loci, researchers have used naturally occurring Cas9 orthologs with different PAM specificities (Cebrian-Serrano and Davies, 2017). The majority of these natural Cas9 variants, however, are less well-characterized, less active in a variety of conditions, and/or more stringent in their PAM requirements than SpCas9.

[00496] Motivated by the limited set of natural Cas9 homologs that have successfully been used for genome editing, researchers have engineered or evolved both Staphylococcus aureus Cas9 (SaCas9) (Kleinstiver et al., 2015a) and SpCas9 (Hu et al., 2018; Kleinstiver et al., 2015b; Nishimasu et al., 2018) to increase their PAM targeting scope. These efforts have led to an expansion of SpCas9’s potential PAM compatibility from NGG to most NG sites (Hu et al., 2018; Nishimasu et al., 2018). However, despite this substantial increase in SpCas9’s DNA targeting capability, non G-rich locations in the genome remain difficult to access, despite their abundance. The restriction on Cas9 targeting is especially problematic when using precision genome editing techniques which require strict placement of the Cas9 in relation to the desired genomic edit, such as homology-directed repair (HDR) (Paquet et al., 2016), predictable template-free end-joining (Shen et al., 2018), and base editing (Rees and Liu, 2018).

[00497] Base editing is a widely used genome editing technology in which a target base is directly converted to another base through deamination of cytosine to uracil (cytosine base editor, CBE) (Komor et al., 2016), or adenine to inosine (adenine base editor, ABE) (Gaudelli et al., 2017) by a Cas9-directed deaminase, ultimately resulting in a C•G-to- T•A, or A•T-to-G•C conversion, respectively. This technology is particularly sensitive to Cas9 positioning: activity for SpCas9-derived editors, for example, is optimal when the PAM is located approximately 13-17 nt away from the target base (Rees and Liu, 2018). In addition, for any given base edit, it may be desirable to screen multiple target sequence windows to maximize on-target activity while minimizing editing of other bases (Jin et al., 2019; Lee et al., 2018a; Xin et al., 2019; Zuo et al., 2019). Taken together, these requirements highlight the major ongoing need to access additional PAM sequences. Here we report the directed evolution of three new SpCas9 variants capable of recognizing NRRH, NRTH, and NRCH PAMs, respectively, where R = A or G, and H = A, C, or T. These variants were evolved through improved phage-assisted continuous evolution (PACE) selections for SpCas9 binding to specific sequences with non-NGG PAMs. We extensively characterized these three new variants, as well as SpCas9-NG (Nishimasu et al., 2018), a previously-reported engineered SpCas9 that recognizes NG PAMs, on 64 endogenous human genomic target sites, as well as a library of 11,776 integrated target sites. The new variants reported here, together with previously reported NG- compatible Cas9 variants, expand the potentially accessible PAM sequence space of SpCas9 to cover the vast majority of NR sequences.

Results

Initial evolution of SpCas9 toward non-G PAM sequences

[00498] Phage-assisted continuous evolution (PACE), a method for the rapid directed evolution of biomolecules, has been used to evolve a wide range of proteins including RNA polymerases (Carlson et al., 2014; Dickinson et al., 2013; Esvelt et al., 2011; Pu et al., 2017), proteases (Dickinson et al., 2014; Packer et al., 2017), antibody-like proteins (Badran et al., 2016; Wang et al., 2018), insecticidal proteins (Badran et al., 2016), metabolic enzymes (Roth et al., 2019), aminoacyl-tRNA synthetases (Bryson et al., 2017), and DNA-binding proteins (Hu et al., 2018; Hubbard et al., 2015). In PACE, a population of bacteriophage (selection phage, SP) is continuously diluted by E. coli host cells (Esvelt et al., 2011). These SP lack gene III (gIII), which encodes the coat protein pIII that is essential for phage infectivity, and instead express the protein to be evolved.

[00499] SP carrying protein variants with desired activity are able to trigger the production of pIII from an accessory plasmid (AP) in the host cells, thus generating infectious progeny and allowing the SP population to persist despite continuous dilution. Conversely, SP encoding inactive variants cannot trigger pIII production, and produce non-infectious progeny that are rapidly diluted out of the system. The SP genome is continuously mutagenized by a mutagenesis plasmid (MP), thus generating diversity in the evolving protein of interest.

[00500] PACE was used to evolve SpCas9 variants with broadened PAM compatibility by linking PAM recognition to SP propagation through a bacterial one-hybrid protein:DNA binding selection (Hu et al., 2018). In this selection system, binding of a nuclease-inactive dSpCas9 variant fused to the E. coli RNA polymerase omega subunit (ώ–dSpCas9) to a target protospacer-PAM sequence recruits E. coli RNA polymerase to drive gIII transcription from an adjacent s70 promoter (FIG.36 (A)). Only SP carrying w– dSpCas9 variants capable of binding to the target PAM sequence will produce infectious progeny phage and replicate during PACE (Hu et al., 2018). Evolving SpCas9 against a mixture of all possible NNN or HHH (H = non-G) PAMs using this selection led to xCas9, which can bind some NG PAMs, but very few non-G PAMs (Hu et al., 2018). We hypothesized that during the evolution of xCas9, the use of a complex mixture of many PAMs reduced the selection pressure for binding activity on any specific PAM. Therefore, we reasoned that selecting for binding to specific PAM sequences in parallel PACE experiments might result in SpCas9 variants with better recognition of non-canonical PAMs.

[00501] To determine which non-G PAMs might be accessible upon extensive SpCas9 evolution, we performed phage propagation assays, which serve as a proxy for a protein’s activity on a defined target, of SP encoding either SpCas9 or xCas9 on host cells containing APs spanning all 64 NNN PAM sequences (FIG.36(B)). While SpCas9 and xCas9 demonstrated phage propagation activity on many G-containing PAMs, SP encoding xCas9 and, to a more limited extent, SpCas9, also showed modest propagation on host cells containing NAN PAM APs (FIG.36(B)). Thus, we decided to focus our evolution efforts on the NAN subset of PAM sequence space.

[00502] We began by using phage-assisted non-continuous evolution (PANCE) (Roth et al., 2019; Suzuki et al., 2017), in which SP are iteratively passaged through serial dilution in

plate wells containing host cells, to evolve either SpCas9 or xCas9 for binding to each of the 16 possible NAN PAM target sequences in parallel (FIG.36(C)). While slower than

PACE, PANCE is less stringent, enabling weakly active variants to replicate (Roth et al., 2019) and can be performed in higher throughput, allowing us to evolve simultaneously

towards many different targets. After performing 19 rounds of serial dilution in PANCE (total net phage replication of ~1038-fold) on each of the 16 NAN PAM variants in parallel, we observed mutations largely differing according to the 3rd base of the NAN PAM targeted for evolution (FIG. 36(D)). For example, variants selected on NAA enriched Gly, Ile, or Lys at position 1333, while those selected on NAT enriched Gln or Leu at position 1335. [00503] Finally, variants evolved to bind NAC simultaneously acquired Gln at position 1335 and Asn at position 1337. Given this early divergence, we decided to divide the evolution of these SpCas9 variants into three separate non-G PAM trajectories: HAA, HAT, and HAC. Because our goal was to evolve SpCas9 to recognize non-G PAMs, we chose to exclude NAG from our targets; additionally, NG-targeting SpCas9 variants have been reported (Hu et al., 2018; Nishimasu et al., 2018), which in theory should allow targeting of sites with NAG PAMs by simply shifting the protospacer sequence by a single nt in the 3’ direction.

New Cas9 PACE selections enable evolution of NAA PAM binding activity

[00504] The NAA PAM trajectory was initially focused on. Despite enriching for multiple consensus mutations in the PAM-interacting domain (PID; residues 1099-1368) (D1135N, E1219V, Q1221H, H1264Y, A1320V, R1333K), our NAA-targeted PANCE evolved variants exhibited low base editing activity when subcloned into C to T base editors (CBEs) and tested on sites containing NAA PAMs in mammalian cells (clone GAA.N1-4; FIG.37C). We hypothesized that evolving increased binding activity might benefit editing efficiencies, and implemented three strategies to increase selection stringency.

[00505] First, we required that the evolving SpCas9 also bind a second, distinct protospacer by using a dual-AP system. In this system, each AP provides one half of split-intein pIII (Wang et al., 2018) under control of the Cas91-hybrid circuit. Binding of the SpCas9 variant to both sites produces both pIII-intein halves, which must be coexpressed to splice and generate functional full-length pIII (FIG. 37A). We chose two variants evolved in PANCE (GAA.N1-2 and GAA.N1-4; FIG.37D and 37B) and subjected them to PACE using this dual-AP system. These experiments, which also targeted a CAA PAM, lead to the acquisition of five additional consensus mutations (A10T, I322V, S409I, E427G and G715C; FIG.44B), which together in clone CAA.P1-1 improved CBE activity on sites with NAA PAMs in mammalian cells 4.2-fold on average when compared to PANCE evolved variant GAA.N1-4 (FIG.37C). [00506] Second, we reasoned that production of large amounts of w–dSpCas9 by the SP might saturate binding to protospacer-PAM sites even if the affinity of the SpCas9 variant for that PAM was modest. Indeed, previous reports have shown that using higher concentrations of SpCas9 can lead to recognition of non-canonical PAM sequences (Karvelis et al., 2015), despite modest binding of these sequences by SpCas9. Unfortunately, as both the promoter and ribosome-binding site for w–dSpCas9 are encoded on the SP, the total amount of w–dSpCas9 produced is subject to selection in PACE and thus falls outside of experimenter control.

[00507] Therefore, we sought to limit the total amount of SpCas9 present in the selection by using a split-intein to divide w– dSpCas9. Here, only the C-terminal segment of dSpCas9 (residues 574-1368) fused to NpuC (dSpCas9C) is encoded on the evolving SP, and the w–N-terminal portion (residues 1- 573) fused to NpuN (w–dSpCas9N) is provided on an immutable complementary plasmid (CP) in the host cells (FIG.37A and 43B). This strategy (hereafter,“split-SpCas9”) allows the total amount of full-length SpCas9 produced in the host cells in PACE to be limited by the expression level of w– dSpCas9N from the CP.

[00508] We subcloned the mutations obtained from clone CAA.P1-1 (FIG.37B), evolved using the dual-AP selection, into the split-SpCas9 format. Four mutations (T10A, I322V, S409I, and E427G) had accumulated in residues 1-573 of this clone. To investigate their effect, we compared the activity of w–dSpCas9N with that of w–dSpCas9N(T10A I322V S409I E427G) (hereafter referred to as w– dSpCas9N-mut) in overnight phage propagation assays using phage encoding dSpCas9C derived from CAA.P1-1. We observed greater phage propagation on host cells with a CP encoding w–dSpCas9N- mut(FIG.43D), suggesting that these four mutations might have a beneficial effect on SpCas9 binding. Therefore, we used w–dSpCas9N-mut in the CP supporting all subsequent evolution efforts.

[00509] We subjected our evolved CAA.P1-1 dSpCas9C to two subsequent PACE campaigns (8 and 3 days, respectively, at average flow rates of 1.3 V/h) using host cells harboring an AP containing an AAA or CAA PAM target site and CPs providing successively decreasing amounts of w–dSpCas9N- mut (see Methods for details). These rounds lead to the accumulation of additional mutations in the PID, including D1180G, which was present in several sequenced clones (CAA.P2-2, AAA.P3-1, CAA.P3-1,2; FIG.37B).

[00510] Among 10 surviving clones randomly chosen for sequencing, we observed 7-17 nonsilent mutations per clone (FIG.37B). From these, the SpCas9 variant CAA.P2-2 exhibited a large increase in mammalian cell base editing activity, with more than double the activity of our previous variants on most NAA sites tested (FIG.37C). Third, to further increase selection stringency, we removed gene VI (gVI), which is essential for phage propagation, (Brödel et al., 2016) from the SP for use as a second selection marker (in addition to gIII) in PACE. This strategy allowed us to combine both selection modifications described above by requiring a split-dSpCas9 to bind each of two distinct protospacers in order to express both gIII and gVI (FIG.37A).

[00511] Thus, three dSpCas9C clones from our previous evolutions (CAA.P2-1, CAA.P2-2, and CAA.P3-1) were subjected to this highest-stringency selection in PACE, resulting in additional mutations in the PID. Most notably, R1114G and L1318S were both highly enriched among sequenced surviving variants, which on average contained 20 non-silent mutations relative to SpCas9 (TAA.P4; FIG.37B). When tested in mammalian cell CBE experiments, these variants showed little editing activity (FIG.37C). We theorized that the large number of mutations present in these highly evolved variants, especially those outside of the PID, might prove deleterious to expression and/or inactivate either nuclease domain. To address this possibility, we performed DNA shuffling of the C- terminal portion (residues 574-1368) of the pool of variants from this final evolution with wild-type SpCas9(574-1368), allowing deleterious mutations to exit while shuffling mutations between the pool members, and re-subjected the resulting library to our most stringent binding selection. This “backcrossing” process led to the isolation of clone TAA.P4s-4 (R1114G, D1135N, V1139A, D1180G, E1219V, Q1221H, A1320V, R1333K) (FIG.37B and 37D), which demonstrated a 1.2- fold increase relative to the previous best PACE mutant across all HAA sites tested amongst our variants (FIG.37C).

Evolution of SpCas9 variants that recognize NAT or NAC PAM sequences

[00512] Based on the outcomes of the NAA PAM evolution campaigns, we approached the evolution of SpCas9 variants capable of recognizing NAT and NAC PAM sites in a fashion that avoids potentially deleterious bystander mutations. To ensure that we started with nuclease-active variants, we developed a modified version of a previously reported (Kleinstiver et al., 2015b) bacterial DNA cleavage selection (FIG.43E and 43F). In this nuclease selection, SpCas9 variants are challenged for their ability to cleave a protospacer-PAM sequence on a high-copy plasmid that also encodes a conditionally toxic gene (sacB). The surviving cells encode nuclease-active SpCas9 variants that cleave the target sequence, destroying the toxic plasmid.

[00513] Thus, we converted the dSpCas9 clones from the NAT or NAC PANCE pools into nuclease- active forms by restoring Asp 10 and His 840, then passed the resulting libraries through the nuclease selection using a TAT or CAC PAM, respectively. From this, we isolated two clones (SacB.TAT-1 and -2; FIG.37E) that exhibited DNA cleavage activity on the TAT PAM with PID consensus mutations of D1135N, E1219V, Q1221H, P1321S, and R1335L, and a third clone that cleaved a CAC PAM with PID mutations N1135D, E1219V, D1332N, R1335Q, and T1337N (SacB.CAC; FIG.37F). We evolved these nuclease-active TAT and CAC variants in split-dSpCas9 PACE using host cells encoding APs with either NAT (AAT or TAT) PAMs or NAC (AAC, TAC, or CAC) PAMs, respectively. These experiments resulted in the enrichment of several additional PID mutations, including R1114G, which arose independently in all three trajectories (NAA, NAT, and NAC) (Figures 37B, 37E, and 37F), suggesting that this mutation may be generally beneficial for modifying PAM recognition by the PID in a manner compatible with NA PAMs.

[00514] Next, we removed gVI from these evolved SP pools and subjected them to additional selection in split-dSpCas9 PACE using the dual-AP system (FIG.37A and FIG.43C). Both protospacers contained either an AAT or TAC PAM for evolution following the NAT or NAC trajectory, respectively. Increasing stringency for the NAT-targeting SpCas9 did not improve activity despite enrichment of several mutations (TAT.P6; FIG.37D and 44A). We therefore selected the most active NAT PAM-targeting variant from the split-dSpCas9 evolution (TAT.P5-1; Figure 37D) to move forward with. This variant contained the 11 PID mutations R1114G, D1135N, D1180G, G1218S, E1219V, Q1221H, P1249S, E1253K, P1321S, D1332G, R1335L (Figures 37E and 37G). PACE of NAC-targeting splitdSpCas9 using dual protospacers and a TAC PAM also enriched for several mutations (TAC.P9; Figure 37G). We shuffled residues 574-1368 of the surviving clones with that of SpCas9 and re-challenged the resulting library with our most stringent binding selection (TAC.P9s; Figure 37G). From the surviving SP pool, we isolated clone TAC.P9s-3 with the PID mutations R1114G, D1135N, E1219V, D1332N, R1335Q, T1337N, S1338T, and H1249R (Figures 37F and 37H).

Mutations outside of the PID

[00515] Structural studies of SpCas9 suggest that residues in the PID mediate PAM specificity (Anders et al., 2014). Indeed, most of the previous efforts to engineer or evolve SpCas9 to accept alternative PAMs have focused on modulating this region of the protein (Kleinstiver et al., 2015b; Nishimasu et al., 2018). However, because our PANCE and PACE experiments allowed mutation of either the entire SpCas9 sequence or residues 574-1368 (in the case of split-intein w–dSpCas9), we observed the enrichment of many where from 3 to 15 mutations outside of the PID. Because many of these mutations fell within the RuvC or HNH nuclease domains, we anticipated that some would negatively impact SpCas9 nuclease activity (Jiang and Doudna, 2017). However, other mutations in the helical domain consistently enriched across several independent evolving populations, suggesting that they may confer a beneficial effect on SpCas9 DNA binding/unwinding. To minimize the deleterious effects from bystander mutation accumulation in the nuclease domains while preserving beneficial mutations in the helical domain, we decided to transplant our evolved PIDs onto a fixed N- terminal sequence that included the mutations T10A, I322V, S409I, E427G that we found to improve phage propagation in the split-dSpCas9 selection (FIG.43D), as well as R654L and R753G, which consistently enriched across multiple independent PACE experiments (Figure 44B).

[00516] The addition of all six NTD mutations to CBEs containing the PIDs of NAA variant TAA.P4s-4 and NAC variant TAC.P9s-3 improved CBE activity in mammalian cells across several sites when compared to SpCas9 variants containing only the evolved PID mutations (Figure 44C). A smaller benefit was observed when the NTD mutations were added to the PID mutations of NAT variant TAT.P5-1 (Figure 44C). We incorporated these six N-terminal mutations into all three final variants, hereafter referred to as SpCas9-NRRH, SpCas9-NRTH, and SpCas9-NRCH, which are the addition of T10A, I322V, S409I, E427G, R654L, and R753G to the evolved PID domains from TAA.P4s-4, TAT.P5-1, and TAC.P9s-3, respectively.

Characterization of PAM specificity through bacterial depletion

[00517] To better characterize the PAM specificities of our evolved variants as nucleases, we performed bacterial PAM depletion using a NNNN PAM library (Kleinstiver et al., 2015b). For comparison, we also performed depletion experiments with SpCas9-NG in parallel. Cells were plated after 1-hour, 3-hour, or overnight expression of the SpCas9 variant from an inducible promoter to assess kinetic differences in PAM sequence preference. Consistent with the eventual cleavage of even modestly recognized PAMs, depletion scores of any given PAM (defined as the frequency of the PAM in the input library divided by the frequency of the PAM post-selection) increased with longer induction times, with the shortest induction times resulting in the most noticeable sequence preferences (Figure 45A).

[00518] For example, at shorter induction times, SpCas9-NRRH exhibited a strong preference for C at the 4th PAM position, a mixed preference for purines at positions 2 and 3 and a moderate preference for G at position 1 (Figure 38A). However, longer induction times resulted in more relaxed preferences at all PAM positions. Similarly, SpCas9-NRCH showed a strong preference for G at position 2 and a moderate preference for pyrimidines at position 4 (Figure 38A) at shorter inductions, but only a mixed enrichment for purines at position 2 was observable at longer induction times (Figures 38A and 45A). Finally, at short induction times, SpCas9-NRTH enriched strongly for G and T at positions 2 and 3, respectively (Figure 38A), but the nucleotide preference at position 2 shifted to a mix of G and A at longer timepoints, suggesting that this variant recognizes and cleaves NAT PAMs more slowly than NGT PAMs. These results also suggest that SpCas9-NRTH may preferentially recognize NGT over NGG PAMs, as the NGT PAMs were more strongly depleted than NGG PAMs (average depletion score of 1394 for NGT compared to 223 for NGG at 1 h induction).

[00519] Interestingly, SpCas9-NG displayed a moderate preference for G at the 3rd and 4 ^th PAM position at short induction times. This finding is consistent with the T1337R mutation in SpCas9-NG, which is also found in SpCas9 VRER and VRQR (Kleinstiver et al., 2015b) and is the basis of the increased specificity for G at the 4th PAM position in these two variants (Anders et al., 2016; Hirano et al., 2016b; Kleinstiver et al., 2015b). Similar to the evolved SpCas9s described here, SpCas9-NG’s PAM sequence requirements also became more relaxed with longer induction times (Figure 45A). Evolved SpCas9 nucleases generate indels at endogenous human genomic loci

[00520] Next, we assessed the activity of our evolved variants in HEK293T cells through indel formation at 64 endogenous target sites spanning all possible NANN PAMs. For comparison, we also tested the activity of SpCas9-NG at these sites in parallel. Generally, each of our variants displayed the highest indel formation activity on target sites containing a PAM it was evolved to recognize, with SpCas9-NRRH and -NRTH showing an average of 23±4.5% and 23±4.1% indel formation on target sites containing NAAN and NATN PAMs, respectively. Sites containing NACN PAMs were edited at slightly lower efficiencies, with SpCas9-NRCH averaging 18±3.4% indel formation. Additionally, SpCas9-NRRH displayed 23±4.3% average indel formation on sites containing a NAG PAM, even though it had not been evolved to bind this PAM sequence (Figure 3B). Indel formation activity of xCas9 was also examined at a subset of NAN sites and found to be minimal (Figure 45B). [00521] Interestingly, we also observed indel formation with SpCas9-NG at some NANN sites. Although its average indel formation across these sites was lower than our evolved variants, SpCas9- NG displayed activity at sites with NANG PAMs (NAAG: 12±1.7%, NACG: 14±3.0%, NATG: 23±3.6%, NAGG: 20±2.5% average indel formation) (Figure 38B). In contrast, our evolved variants showed the lowest average activity at sites with PAM sequences with a G at position 4, and the highest at sites with a non-G (H) at this position (27±5.0%, 27±4.7%, 24±3.9%, and 27±4.4% average indel formation for SpCas9-NRRH, -NRTH, -NRCH, and -NRRH on NAAH, NATH, NACH, and NAGH PAMs, respectively) (Figures 38B and 38C). These results are consistent with the sequence preferences predicted by our bacterial PAM depletion experiments and suggest that our variants and SpCas9-NG exhibit complementary PAM specificities, especially with respect to non-G versus G bases at the 4th position.

[00522] We also tested the indel formation activity of our evolved variants and SpCas9-NG on a number of endogenous target sites containing NGN, rather than NAN, PAMs. While treatment with SpCas9-NG gave rise to robust indel formation on most NGN PAMs examined (48±4.4%), SpCas9- NRTH and -NRCH showed slightly higher activity than SpCas9-NG at NGT and NGC PAMs, with 68±3.9% and 42±2.5% average indel formation, respectively (Figure 45C). Consistent with the PAM depletion assay results, a preference for H at position of the PAM was observed in these experiments for SpCas9-NRTH and -NRCH.

DNA specificity of evolved SpCas9 nucleases

[00523] As broadening the PAM targeting capabilities of various Cas9 has been shown to increase the proportion of genomic off-targets edits (Kleinstiver et al., 2015a; Nishimasu et al., 2018), we performed genome-wide, unbiased identification of double-strand breaks enabled by sequencing (GUIDE-seq) using SpCas9, SpCas9-NRRH, -NRCH, and–NRTH in U2OS cells (Tsai et al., 2015). For comparison, we also analyzed xCas9, which was previously shown to possess reduced off-target activity (Hu et al., 2018). These experiments showed that, when targeting the highly promiscuous HEK site 4 (HEK4) (Tsai et al., 2015), our evolved variants displayed comparable or better on-target activity (8.8%, 22.5%, and 7.8% on-target reads of total reads for SpCas9-NRRH, -NRTH, and - NRCH, respectively) when compared to SpCas9 (5.1% total reads) (Figure 38D and 45D). This is similar to xCas9, which also exhibited improved on-target activity (12.7% total reads) relative to SpCas9 (Figure 38D and 45D) (Hu et al., 2018). Interestingly, our variants primarily displayed off- target activity at sites containing PAMs consistent with their evolved preferences. For example, the most prominent off-target for SpCas9-NRRH occurs at a site bearing a CAA PAM (10% total reads), SpCas9-NRTH at a GGT PAM (10.2% total reads), and SpCas9-NRCH at a TGC PAM (9.9% total reads) (Figure 45D).

[00524] Various off-targets were also observed at sites with NRN PAMs, such as GAA, GAT, and CAG, for these evolved SpCas9s (Figure 45D). Taken together, these results suggest that our evolved variants may have similar or increased DNA specificity compared to SpCas9 on sites with NGG PAMs, and due to their altered PAM specificities may access a different set of off-target sequences. Evolved SpCas9s support cytosine and adenine base editing

[00525] Since expanding the targeting scope of base editing was a major motivation behind our efforts, next we determined the ability of our evolved SpCas9s to support both cytosine and adenine base editing. We generated CBEs by incorporating our evolved variants into BE4max (Koblan et al., 2018) (hereafter referred to as“BE4”) in place of SpCas9 and tested their activity at the same 64 endogenous NANN PAM sites examined above for indel formation. As with their nuclease forms, each of the three evolved CBE variants showed the highest average activity on sites containing the PAM it was evolved to recognize. BE4-NRRH and BE4-NRTH performed best on NAAN and NATN PAMs with an average of 12±2.1% and 17±2.3% C•G to T•A conversion, respectively. CBE activity on NACN PAMs was slightly less efficient, with BE4-NRCH enabling the highest editing activity at these sites at an average of 11±1.7% base conversion. Both BE4-NRRH and BE4-NG (generated from SpCas9-NG) edit NAGN sites similarly, at 12±2.8% and 11±2.1% average base conversion (Figure 39A).

[00526] Improved editing activity was again observed on sites with NANH PAMs, where C•G to T•A conversion at NAAH, NATH, NACH, and NAGH sites increasing to 14±2.4%, 21±2.5%, 13.0±2.0%, and 14±2.3 for BE4-NRRH, -NRTH, -NRCH, and -NRRH, respectively (Figure 39A and 39B) . BE4-NG performed well at sites containing NANG PAMs, with 14±1.3% average editing (Figure 39A). Average CBE editing efficiency across all 64 sites was lower than that of indel formation, likely due to increased requirements for efficient base editing such as sequence context and position of the C within the window.

[00527] These editors also function on sites with NGN PAMs, editing at 17±2.3%, 9.1±3.0%, 19±2.9% and 20±4.0% for BE4-NRRH, -NRTH, -NRCH, and -NG, respectively (Figure 46A).

Finally, we also generated ABEmax (Koblan et al., 2018) variants (hereafter referred to as“ABE”) from SpCas9-NRRH, -NRTH, -NRCH, and SpCas9-NG, and tested adenine base editing at 54 endogenous loci. We observed that the newly evolved variants are also compatible with adenine base editing, exhibiting similar performance on a subset of sites containing NAN and NGN PAMs as we observed for the corresponding CBEs and nucleases. For example, ABE-NRRH, -NRTH, -NRCH, and -NRRH edited most efficiently at NAAH, NATH, NACH, and NAGH PAMs, with 16±2.6%, 24±2.9%, 13±2.2%, and 26±3.5% base conversion (Figure 39C and 46B).

[00528] The scope of base editing is limited by the requirement that the target base be located within the canonical CBE or ABE editing window (approximately protospacer positions 4-8, counting the PAM as positions 21-23). The evolved variants SpCas9- NRRH, -NRCH, and -NRTH, together with SpCas9-NG and xCas9, expand the targeting scope of SpCas9 to sites to cover the vast majority of NR PAMs, greatly increasing the fraction of known human pathogenic SNPs that can in theory be corrected by base editing. [00529] Among all pathogenic SNPs in the ClinVar database (Landrum et al., 2014) that are corrected by C•G to T•A conversion, 95% are targetable in principle with CBEs derived from SpCas9-NRRH, -NRCH, -NRTH, or SpCas9-NG/xCas9. Likewise, 95% of pathogenic SNPs in ClinVar that are correctable via A•T to G•C conversion can now be targeted with ABEs derived from the same set of Cas9 variants (Figure 39D).

[00530] In addition, these new variants greatly increase the number of possible protospacers available for targeting a given SNP for base editing: on average, there are 2.7 protospacers per pathogenic SNP targetable with CBE and 2.7 protospacers for those targetable with ABE with NR PAMs, compared to 1.7 targetable with CBE and 1.7 targetable with ABE, respectively, when using NG PAMs, and 1.3 and 1.3 protospacers available when using NGG PAMs only to target CBE and ABE, respectively (Figure 39E).

[00531] Since many pathogenic SNPs correctable by current base editors contain multiple targetable bases within the editing window (Figure 46C), expansion to NR PAMs enables multiple targeting strategies for a given SNP to optimize editing of the desired base, as we explicitly demonstrate below.

[00532] Collectively, these findings establish that evolved Cas9 variants SpCas9-NRRH, -NRCH, and -NRTH are compatible with both CBEs and ABEs, and thereby expand the targeting scope of base editing substantially.

Characterization of evolved SpCas9s on a human cell library of 11,776 integrated target sites

[00533] To comprehensively profile the PAM preferences of these variants, we analyzed the CBE efficiencies of our three evolved variants, SpCas9-NG, and SpCas9 on a library of 11,776 unique sequences in human cells. This library was designed using 46 distinct protospacers derived from sequences found in the human genome, each with different sequence contexts surrounding a fixed C at protospacer position 6, counting the PAM as positions 21-23. Each protospacer is adjacent to a PAM sequence of 4Ns, and is additionally flanked with designated primer binding sites for amplification for highthroughput sequencing (HTS) analysis (Figure 40A).

[00534] Due to the very large number of target sites (Figure 47A), characterization of our evolved variants in this library format revealed PAM preferences in finer detail when compared to our bacterial depletion and endogenous mammalian genomic site editingexperiments (Figure 40B).

Consistent with these previous experiments, our evolved variants exhibited the highest editing activity when either A or G was present at the 2 ^nd PAM position (Figures 40C and 47B), when the 3rd PAM base was the one on which it was evolved (Figures 40D and 47B), and when a non-G was present at the 4th position of the PAM (Figures 40E and 47B). BE4-NG also showed the highest editing activity when either A or G was present at the 2nd PAM position (Figure 40C), but, unlike our evolved variants, was most active when a G was present at the 4th position of the PAM (Figure 40E and 47B) or when G or T was in the 3 ^rd position (Figure 40D). In contrast, we found that BE4 editing efficiency at sites containing its canonical NGG PAM or its alternate NAG/NGA PAMs showed virtually no dependence on the 4th PAM nucleotide (Figure 40B). BE4 also showed some editing at sites containing a NCGG or NTGG PAM, which could be due to PAM slippage (Jiang et al., 2013), resulting in binding to a canonical NGG sequence.

[00535] Interestingly, our evolved variants and SpCas9-NG exhibit some level of editing activity at many more non-canonical PAMs when compared to SpCas9, supporting their broadened PAM scope (Figure 40B). Finally, both SpCas9-NG and our variants (most notably BE4-NRRH) performed best when a G was present at position 1 of the PAM and worst when a T was at this position; in contrast, BE4 exhibited only a slight preference for G at position 1 (Figures 40B, 47B, and 47C). Taken together, these results strongly support the PAM preferences observed in our bacterial depletion and endogenous mammalian genome editing experiments: specifically, recognition of NRRH, NRCH, NRTH, and NRNG PAMs for SpCas9-NRRH, -NRCH, -NRTH, and -NG, respectively. [00536] Additionally, this library allowed us to investigate the tolerance of our variants to mismatches between the sgRNA and the target DNA sequence. The U6 promoter, commonly used to express sgRNAs in mammalian cells, initiates transcription with a 5’ G. If a G is not natively present at the 5’ end of the protospacer, guide sequences are typically either extended to the next native G, or simply transcribed with a mismatched 5’ G at position -1 of the guide sequence. However, high- fidelity (HF) SpCas9s (Chen et al., 2017; Hu et al., 2018; Kleinstiver et al., 2016; Lee et al., 2018b; Slaymaker et al., 2016), which are less tolerant of mismatches between the protospacer and sgRNA, generally exhibit decreased efficiency when using a 21 nucleotide (nt) guide with a mismatched 5’ G (Kim et al., 2017b; Zhang et al., 2017). Because PACE has previously led to SpCas9s with HF properties (Hu et al., 2018), we sought to determine if our new variants shared the same

characteristics.

[00537] We investigated the average base editing activity of our evolved variants across all 11,776 library sites containing either a 20 nt protospacer with a matched 5’ G (“20- matched”), a 21 nt protospacer with a matched 5’ G (“21-matched”), or a 21 nt protospacer with a mismatched 5’G (“21- mismatched”). Our three evolved SpCas9 variants and SpCas9 all showed the highest base editing activity with a 20-matched sgRNA (Figures 40F, 40G, and 47D-F; however, interestingly, SpCas9- NG performed best with a 21- matched sgRNA (Figures 40F and 47D-F). When examining all NRNN PAMs, our variants and SpCas9 also showed a significant decrease in base editing efficiency when the sgRNA protospacer was increased to 21 nt, regardless if the 5’ G was matched with the target sequence (Figures 40F, 40G, 47D, and 47E); in contrast, for SpCas9-NG this was only true when the 21-mismatched sgRNA (Figures 40G, 47D, and 47E). The magnitude of this decrease was similar to or greater for our evolved variants (SpCas9-NRRH: 23±2.7%, SpCas9-NRTH: 12±2.9%, SpCas9- NRCH: 14±2.9%) when compared to SpCas9 (13±5.3%). In contrast, SpCas9-NG demonstrated a preference for 21-matched sgRNAs, leading to an average 18.5±5.4% increase of editing efficiency when compared to 20-matched sgRNAs (Figures 40F, 47D, and 47E); however, a decrease in editing efficiency was still observed with 21-mismatched sgRNAs (7.3±3.2%, Figures 40G, 47D, and 47E). Interestingly, the deleterious effect of using a 21 nt protospacer on the editing efficiency of our evolved variants and SpCas9 is lessened when targeting sites with NGNN or NGGN PAMs (Figures 40F, 40G, 47D, and 47F). This is especially true for SpCas9, which shows no significantly decreased base editing activity on sites with a 21 nt matched or mismatched protospacer when the PAM is NGG (Figures 40F and 47F). Together, these results suggest that our evolved variants are somewhat sensitive to the use of 21 nt sgRNA protospacers, and that this sensitivity is exacerbated by the presence of 5’G mismatches. Additionally, these experiments suggest that the optimal sgRNA protospacer length for SpCas9-NG may be longer than 20 nt.

Evolved SpCas9s enable efficient base editing of a pathogenic SNP

[00538] To demonstrate the utility of our evolved SpCas9 variants in a disease-relevant context, we targeted the Glu to Val point mutation at amino acid 6 of b-globin (HBB), which results in the HbS allele that is the most common cause of sickle-cell anemia (Rees et al., 2010). The HbS mutation arises from a GAG (Glu) to GTG (Val) codon change that cannot be reverted through current base editing technologies. However, this SNP can be edited with ABE to a GCG (Ala) through A•T to G•C conversion on the opposite strand (Figure 41A). The resulting HBB E6A genotype, known as the hemoglobin Makassar allele (HbG), has been reported as clinically normal in homozygous and heterozygous individuals (Quentin Blackwell et al., 1970; Sangkitporn et al., 2002; Viprakasit et al., 2002).

[00539] Unfortunately, the only NGG or NGN PAMs available at this site place the target A at either protospacer position 2 or 9, respectively, which fall outside the optimal editing window for ABE (positions 4-7) (Rees and Liu, 2018). However, two alternative target protospacer sequences using a CAT or CAC PAM place the target A at either position 4 or 7, respectively, with a bystander A present at either position 6 or 9 leading to a silent CCT to CCC (Pro to Pro) mutation. Thus, we tested the ability of our evolved variants, along with SpCas9-NG, to convert the sickle-cell SNP to the Makassar mutation using these two protospacer sites with non-G PAMs. We transfected ABE-NRRH, -NRTH, and NRCH, or ABE-NG into HEK293T cells with homozygous GAG to GTG mutations at codon 6 of HBB (Figure 48A). While ABEs derived from the SpCas9 variants evolved in this study supported substantial (14-55%) A•T-to-G•C conversion using guide RNAs targeting either the CAT PAM or the CAC PAM site, ABE-NG edited efficiently (40±0.2%) only using the protospacer sequence containing a CAT PAM (Figures 41B and 41C), perhaps due to the presence of a G at the 4th position of the CAT PAM, which improves SpCas9-NG’s recognition of NAN PAMs (see above).

[00540] Unfortunately, editing using the CAT PAM protospacer occurred primarily at the silent bystander base (position 6), with the target A (position 4) showing less than 10% editing across all four ABEs tested (Figures 41B and 48B).

[00541] Target base conversion of GTG to GCG in codon 6 of HBB using the CAC PAM protospacer, however, was much more efficient. As expected, ABE-NRCH showed the highest editing activity, with 41±3.8% base conversion at the target A (position 7) and 13±3.2% at the silent bystander A (position 9). ABE-NRRH and ABE-NRTH achieved 29±4.3% and 14±2.8% conversion, respectively (Figures 41C and 48C). In comparison, ABE-NG showed negligible (1.0±0.5%) target base conversion activity at this site (Figures 41C and 48C). Collectively, these results demonstrate that our evolved SpCas9 variants enable efficient base editing of previously inaccessible disease- relevant SNPs using non-G PAMs, and furthermore highlight the utility of evaluating multiple protospacer/PAM sequences for targeting a desired SNP.

Discussion

[00542] Here we report three new variants of SpCas9, evolved using phage-assisted continuous evolution (PACE), that are capable of recognizing NRRH (SEQ ID NO: 149), NRCH (SEQ ID NO: 150), and NRTH (SEQ ID NO: 151) PAM sequences. As our initial experiments suggested that increased selection stringency may be necessary to produce SpCas9 variants that were highly active on non-G PAMs, we developed several improved selection strategies for evolving Cas9:DNA binding. Specifically, by increasing the number of target DNA protospacer/PAM sites that must be recognized by the evolving SpCas9 through use of an additional PACE-compatible selection marker (gVI), and limiting the total concentration of full-length SpCas9 in the host cell through use of a split- intein strategy, we were able to select for variants that efficiently recognize a desired PAM while reducing the probability of evolving undesired recognition of specific protospacer sequences. These improved selection strategies should be applicable to a majority of Cas9 orthologs, and enable the further evolution of Cas9 variants capable of targeting a wide range of PAM sequences.

[00543] From our initial experiments evolving SpCas9 for binding activity on all 16 individual NAN PAMs, we were able to identify three distinct groups of consensus mutations that conferred binding activity on NAA, NAT, and NAC PAMs, respectively (Figure 1D), leading us to split our subsequent evolutionary efforts into three separate trajectories to target these specific PAMs. Accordingly, the diverging consensus mutations of our evolved variants give insight to potential modes of PAM interaction.

[00544] SpCas9-NRRH, evolved to bind HAA PAMs, acquired a mutation at R1333, which in SpCas9 contacts the 2nd guanine in its canonical PAM, but not R1335, which contacts the 3rd NGG guanine (Figure 37B and 37D). The R1333K mutation likely allows SpCas9-NRRH to accept both A and G at the 2nd PAM nucleotide, while the preservation of R1335 may explain why this variant recognizes both NAA and NAG PAMs. On the other hand, SpCas9-NRTH (evolved to bind HAT PAMs) preserves R1333 but eliminates R1335 through mutation to a Leu (Figure 37E and 37G). Interestingly, SpCas9-NRTH shows a strong preference for T in the 3rd PAM position and appears to have lost some recognition of the wild-type NGG PAM (Figure 40B). Finally, SpCas9-NRCH displays altered interactions at both R1335 and T1337 (Figure 37F and 37H); the T1337N in particular may form contacts with a 4th PAM nucleotide to compensate for weakened binding interactions with the HAC target PAM. [00545] In addition to alterations at residues responsible for direct contacts with PAM nucleobases, we observed a number of additional mutations which we suspect modulate more general interactions with the target- and non-target DNA, including R1114G, E1219V, Q1221H, and D1135N (Figure 37B, 37D-H). Residue E1219 forms hydrogen bonds with R1335 in SpCas9, and mutations at this residue are thought to destabilize the interaction between R1335 and the 3rd PAM guanine. Mutations at residue D1135 have been previously reported and are thought to modulate interactions with the sugarphosphate backbone of the non-target DNA strand; R1114G and Q1221H may alter similar interactions. Finally, we observed mutations in the helical domain of Cas9 that arose in several independently evolving populations (Figure 44B).

[00546] These mutations, when added to the N-terminal region of NRRH and NRCH, improve their recognition of non-G PAMs in base editing experiments (Figure 44C), and may contribute to increasing the overall DNA binding/unwinding activity of these variants. Along with bacterial PAM depletion and mammalian cell genome editing on endogenous genomic sites spanning all NANN PAMs, we characterized our variants and SpCas9-NG using a 11,776-member

sgRNA/protospacer/NNNN PAM library that was genomically integrated into HEK293T cells. The large number of sites examined greatly increases our ability to confidently profile the editing activity of these proteins using all NNNN PAMs in a human cell context, and illuminated the sequence preferences of these Cas9 variants, including previously uncovered activity of SpCas9-NG on NANG PAMs.

[00547] Both our bacterial PAM depletion experiments and mammalian library data demonstrated that our evolved variants display a different 4th base PAM preference (H) compared to SpCas9-NG (G), suggesting that they may have complimentary utility. While further investigation is required to explain the 4th base preferences of our mutants, crystal structures of SpCas9-NG and other previously reported evolved SpCas9s (VRER/VRQR) suggest that the T1337R mutation in these variants may create a direct interaction with the 4th base G (Anders et al., 2016; Hirano et al., 2016b; Nishimasu et al., 2018).

[00548] Additionally, both SpCas9-NG and our variants display a moderate preference for G at the 1st PAM position, whereas this preference in this position in SpCas9 is virtually nonexistent (Figure 47B and 47C). Because of these numerous sequence preferences, we suggest screening all variants reported here along with SpCas9-NG when optimizing targeting efficiency on sites with NR PAMs, and provide a recommended list of SaCas9 and SpCas9 variants to test for targeting any given NRNN PAM (FIG.42). However, we note that other Cas9 orthologs and related CRISPR effector proteins not included here have been also been shown to mediate genome editing in mammalian cells (Chatterjee et al., 2018; Cong et al., 2013; Edraki et al., 2019; Esvelt et al., 2013; Harrington et al., 2017; Hirano et al., 2016a; Hou et al., 2013; Kim et al., 2017a; Zetsche et al., 2015). Our evolved variants, along with SpCas9-NG, expand the utility of SpCas9 towards disease-relevant genome editing applications. Access to a broad range of PAMs is especially essential for base editing, as illustrated by our experiments targeting the sickle cell mutation of human b-globin. While ABE-NG was able to bind to this locus using a CATG PAM, the majority of base editing we observed occurred at an off-target A within the window (Figure 41B). However, we were able to achieve high levels of conversion at the correct base and lower levels of off-target editing with our evolved variants by using an adjacent CACC PAM (Figure 41C). Notably, the sickle cell SNP occurs within the optimal ABE window for both sgRNAs tested, suggesting that it may be beneficial to assay several protospacer sequences for a single target. Expanding the PAMs accessible by Cas9 variants to NR increases not only the number of targetable pathogenic SNPs (Figure 39D), but also the number of possible sgRNAs that can target an individual SNP (Figure 39E). Additionally, although only results from indel formation and base editing are shown in this work, we anticipate that our evolved variants should be compatible with the majority of Cas9-associated genome editing technologies. Access to NR PAMs should benefit all precision genome editing applications, including other base editing applications, HDR, and predictable template-free genome editing.

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GIRDRI ^L O N T N T N N N N ^u _g T M A F D W T A D R W I N ^A P _G T _Q ^V

G H N _Q ^S I _G ^T A ₆ ^W

0 ^{5 0} _{1 7} ^{. .} _{7 5} ⁷ 7 _{8 9 0 1 2 3 4} ⁹ _{9 6}

4 ₁ ⁴ _{1 1} ^{4 4} _{1 1} ⁵ ₁ ⁵ ₁ ^{5 5} ₁ ⁸

1 ¹ ₈

B ₇ ⁴

EVP ^{S D K} _Q EDKAK T ^P VKF _{G Q} ^R YAIKL _S ^D F _G ^L KF _G ^D _Q ^R YAIKL _S ^D F _G ^L _S ^I ELIVI L _G ^R ILKF _G ^D _Q ^R YAIKL _S ^D F _G ^{L E} VL _S HVKEKA _S ^V I _G EKK KVYNKANNTKK VYNKANNTYDA VI ^L D SVTKITKK VYNKANNT SA PINKY NFFNI I _Q ^I RTTEV RVI ^I K TTEV KVI _G ^Y EKDDIDLF ^I K I TTEV PN _S ^I LLALY _S ^L ERIDR _S MALFKPV _G ^T KY ^I I _Q R SMALFKPV ^T RVI GKY KILAEL VWDL ^I I _Q R SMALFKPV ^T RVI GKY VLEATEREL EKNHHLLYLKEVP _Q ^S HHLLYLKEVP ^S D ^{N N} FL ^G Y Q KVKHHHLLYLKEVP ^S NY LAKELN ^K N GIK LRALDERH L _S ^K HRALDERH VL ^K _{Q S} HA _{G G G} ^Y ND ^D VIKIRALDERH VL ^K _Q K _S H DA _S EDF KHTDY _S ^K LDLNEYE ^E V SA YE ^E A PIAFFNWH ^G _{S S} LE VIDLNEYE ^E A PI SDF ^N LL _Q ^L E TR ADRLE _G ^R PN ^I PIDLNE SLLTADRLE ^R _{S G} PN _S ^I LLPI ^L KPY R _G ^E ENTADRLE ^R _{S G} PN _S ^I LL KH _G VRLN _G ^T RE ^E YDT QKN LLN IMVLEAT GA _G ^G ETIEETN _G ^N YDL _S ^L MVNY ^N LLN ^L IMVLEAT ITKE SMVNY LA ^V P _G T ^V R QN GHN _Q ^S I _G ^T AIL ^N LLN GYDL ^L IMVLEAT SMVNY LA RH ^K E QK ^V E GAD ILTL IDKHEK ^K LA _G YDL SEDLIDKHEK A _S ^K EDHRKDT K _G ^E _G ^Y _Q ^A LIDKHEK A _S ^K ED NH _Q ^T L R _G ^Y ELEY ^V L GVLDVKRV ^D A SDF KRV _S ^D DF DNKEVLDVKRV _S ^D DF KYV ^T AV E _S DYTKEYI IKRYLPDL ^N LVLDV PDL H ^N L GV ^I EKFE _S ^{L K} D QL GH NTARKRYLPDL H ^N L GV DNE _G TIKILIEE _G ^N VFLTLLEE ^K H GA ^G _G VKRYL G EE _G ^K A _G ^G VK ^E F GI ^E AI SND _Q ^E EEEIFLTLLEE _G ^K A _G ^G SNT V RKPTRKDDEVFDRH ^K EFLTLL FDRH ^K E QKKKPEKFEDDILPKDDEVFDRH ^K E QK RIK ^A YVE SRDEL _S ^N EK A EKLVNH ^T _Q KKDDEV QL ^K A EKLVNH _Q ^T L RD RRKVYLFK KLVNH _Q ^T L TEKAKRLN NT ^M EY SEL _S ^K K _S ^K TVKYV _S ^T _S K _S ^K TVKYV ^T KE ^L K QYTDFYKPDD ^K A SK ^K E S ETVKYV ^T LRVLRTAN _Q ^I EY D ^T E LK E ^E _{S G} TKEAKMETMTRIRPD ^T NLK NE ^E _{S G} T VVIMDE LE _Q ^T _S ^{K E} P ^L _G NLK E _G ^E TPD ^T E TV ^D N SNT YKVIEWV NKPHV ^L _{G Q} DPTV _S ^D NT KKNRIY _S ^K DIRI ^A Y _G V QKNK ^T _Q DPTV ^D N SNT YV ^L _G N SLMLL RIK _S ^A RK ^T _Q DP SLMLL RIK _S ^A RPLLPA ^L D S MRNKK _S ^T LMLL IK ^A Y SR NY KTDNNEN KYIYDKKNV _Q ^T TEKAKYDKKNV _Q ^T TEKAKA NLF _S ^G D _G ^R D ^{V F} _Q ^R TI L R _G ^R ELKEVAEKILLRVLREVAEKILLRVLRM _S ^F E ^R IKNYDKKNV ^T R QTEKAK S ^E EYEVAEKILLRVLR I _Q P _G D ^R A _Q ^{E KK} EPIDLDLDD VVIMDDLDLDD VVIMDKEL _Q ^{Q R} ID SEH _Q ^N D _G F DLDLDD VIMD SF NF ^I _{S G} NT _{Q G} FNLTKEIFE _G ^I KKNRITKEIFE _G ^I KKNRIDERR ^V LN ^A DD _S ^M EY ^I YLMK KAPNLKNY LKNY L ^N IL G _S ^S _S TKEIFE ^I V GKKNRI DKLLK ^Y _{Q G} EL EA ^M KDI QENVRLKTIKD ^V KTIKAPN Q TVRLKTIKD ^V KTD Q TDR ^R V SLRD ^L Y QY ^I A _S LIKAPNLKNY QLRVVRLKTIKD ^V KT KRVEF D _S ^E NLN NALDIMDI ^F P _G ^R DALDIMDI ^F P _G ^R DDH AA ATEKALDIMDI ^F _{Q Q} P ^R T GD LFKFA ^V K S ANINE _G ^D Y HFFREA ^I _{Q S} F EA ^I _{Q S} F F _S ^K KL ^F ML CFYVIMD REA _S ^I F NF F ^D R AT _S ^T NLMLM ^W Y KENPDD ^M NF HFFR SEY _G ^W Y KENPDD ^M NFK SEYY EIL ^W HFF GY ENPDD _S ^M EY S _S V _S ^L P YN V _Q ^{Y F} _{G S} I _S ^N YIE DKLLK I _S ^N YIE DKLLKD ^F LL ENLH SRL _G ^P IRKKTTN ^N K IE KLLK QVTY ^I L AT ^K I QHKEA _S ^V TKFFE _G ^S KRVEF _S ^V TKFFE _G ^S KRVEFID TVKNETK ^V I _S Y STKFFE ^S D GKRVEF PLAK ^A _G E GI YLAKKMINPFE NALFKFANPFE NALFKFADD _S ^A LYKA F ^I A GDNPFE V FPLD _G ^N KEDKAIF YNE _Q ^S DLF R A YNE _Q ^S DLF R AHVL F _Q ^N _Q ^I FLA ^S NALFKFA QDLF I _S ^K DLN T _S P _G ^T KP ^{L F VE} KLE _G ^T KP LN ^D V ^{L A} LN ^D V _S PDKI ^D Y QPY _G NLL ^T YNE GKP ^D R AK T _G ^L D _{S Q} ^K F STDK ET _S ^Q _S ^A FA ^S _{S Q} VTY ET _S ^Q _S FA ^S _{S Q} VTY AAHID ^L R QTMEIIET _S ^{Q A} LN ^S _S V ^L A SP SFA _Q VTY DL ^R K GILLERINELL ^A I QAH ^L A ^A DIPLAK ^A I GDH A DIPLAK ^A K GYMKHRE _S ^D TEIKVDH VTKITIELDK Y _G KHV FPL Y _G ^{L A} KHV FPL EAEFKKNV ^A DIPLAK _G ^A DIDLFYVE E ^Y K SK ^K _{Q S} ^N _G ^L A ^G _{G G} KDEI _S ^K DLN _G ^L A ^G _G L _G KDEI _S ^K DLN _G ^{D N V} R ^L Y ^L A G _G KHV L _{S S} A _G ^G KDEI ^K FPL SDLN YVWDLNEE _S ^E RIWYI ^I V _S ^L DDKHAK KHHK ^N DDT SVYL ^L LE QFV _Q YK ^K _{G S} V _S ^L DDKHHK KT DKVKHRNP ELIVI DL ^R KT V _S DD GIL _S ^I ELIVI DL ^R KTD GILHF RIKDPRFLF _S ^I ELIVI L _G ^R IL SVIKIKVF ^S A QL ^K E SK ^T K _{S Q} KYDA I _S ^L VTKITYDA I _S ^L VTKITDI _S ^G KKVLHKFK DA I ^L D SVTKIT LE ^E VIMNYYE PLKVI ^Y V GEK DIDLFKVI ^Y V GEK DIDLFK Y ^E Y SKVI ^Y V GEK DIDLF ⁰ RR _G ENHH II ^D F SIDKKILAEL _G ^D YVWDLKILAEL _G ^D YVWDLY ^E AIETIEI QN VTK K _S ^K ILAEL _G ^D YVWDL ₀ NITKE ^T TI HKD ^N FL VKHD L VKHDLI ^M I SKK L _G ^F A ^I K QD L VKH O I L E Y A _G ^{S V} _{C G} H L I ^S F S D H A M _G ^N _{G G} ^Y N D _G ^{Q D} K S V I K I M _G ^N _G ^{N Y} F G N D _G ^{Q D} K S V I K I M Y P A E R _G ^K I A T _G ^K E M _G ^N _G ^{N Y} F G N D _G ^{Q D} K S V I K I ₆ ^W

0 ^{5 0} _{1 7} ^{. .} _{7 5} ⁷ 5 _{6 7 8 9} ⁹ ₉ 5 ₁ ⁵ ₁ ⁵ ₁ ⁵ ₁ ⁵ ₁ ⁸

1 ¹ ₈

B ₇ ⁴

KK _Q ^Y TELALPKN _S ^K K _S ^{K T} PLPTL _G ^Y EKDDIDLFFKDRDKT _Q ^W F _G ^N F KF _G ^D _Q ^R Y II KEKK PD ^T ETVKYV _S TF GNLK E _G ^E T E ^E DPL SNLR TI _G ^{D R} NFM QFDEKLVP V ^L DPTV ^D N SNT Y A _G ^{N R} DY ^Y E AEL YVWDLLVYAPDIN FI KK KV CDR _Q I L _Q ^G VKHRINEFEEE _G ^Q _Q RT KHAKIRVWEEA K ^T _{Q S} LMLL ^T RIK _S ^A R ^F LVR Q EKKLDLY ^Y F GND ^D R SVIRI HADYFREV ^G E ^I I ^I GE _G MALF KAERTYVFPDV YDKKNV _Q TEKAK ^N R SYD _Q ^I EMMKR H _S ^G LE H T YE HHLLY SLALYN ^{I S} YAV EVAEKILLRVLRFKDKDIV M _S ^{G L} NW Q KPY ^E VI _G ^S L _S ^N D _G ^{T I} VP ^{I R} _S VL _C KD RALDE TALYRE _{S G} KTY DLDLDD ^I VVIMD LVYAPKK _Q FFI T ^V RR _G ENW AFVTILVAHL DLNEY DLLNELKMAIK TKEIFE _G KKNRI RI TN M _Q ^S I ^T _Q NITKEM GAIL ^{Y A} HLEKNDLLIVY TADRL GYDNYRP PNLKNY T H ^N EFK SPYDI _G ^G _G ^G L DT ^E YLAKY VYDE LLN FVNALRK ^K MLD IKA QIVA VRLKTIKD ^V K T _G ^S H T E _S ^E IYI FE _S ^{L K} DK _{G G Q} H QLDNKE IVLMI _Q ^A RAAY _G ^N YDL _S ^L VLLD K ILAF ALDIMDI ^F _Q D WL _S ^D D ^T E CFEPLKD F L TAR _G ^N LI IWNDRR LIDKH KRDI _S ^L I _G ^Y VN FREA ^I _Q P _G ^R SF F LAFV VVAHD I ^E A SND ^E N QEEEIKRD ^L R GEK DHYK VLDAK MLD AA ^Y E SM ^W HF GY ^N KENPDD ^M N SEY HLKK ^Y V ST DILPKPTKIE _G ^I KK KRYLP KDE ^K HLM QKKV _S YIE DKLLK YLERL ^I VVVL EKFED QLI ^D N KRRKVYLFKLD I IR ^F A SHNL FLTLL KAYLP ^E VEI SVVK ^V I STKFFE _G ^S KRVEF _G ^K IK LVY _S D YTDFYKPDDLA _G ^D Y _G ^F LM KDDEV TPTIL ^R K GIPAAD NPFE NALFKFANLI ^I MD CRY RARY KMETMTRVREKKKE ^L KDH QIDFPA V EK PRDEVEI E _Q ^S DLF ^E NDN EKYAYAKDVA _S ^K K _S ^K VD EPFE ^L NKF _{Q G} LAL ^T YN GKP ^D R ARR KKI ^S KIIWDHK ^D EWV Q PA ^L DNKPHY S MRDKHKVFT TY PD ^T E KN _G ^K TEIDNYYE IET ^Q _S ^A LN P KP _{S S} FA ^S _S V _S ^L QVTY YN ETTVTA DH A ^A MDDV N ^{G F} ANK LF _S D _G ^R KNEN ^N PIN SHVY D ^R I S EYD ^E EA _S LIAI V ^L _G N DA _S ^F PPLIKD ^G K GF ^{L A} DIPLAK _G LA Y _G ^F E _G ^I DHPI _Q ^{Q R} I SEH _Q ^N D _G ^E F ^E _Q EDA _G ^S A LK ^T _Q DP SLML CAVINA ^S D QRT _S ^E KYDKKN DLL RHYE ^L Y _{G G} A ^G _G KHV FPL RK _Q ^G KEIR GKDEI _S ^K DLN HEKYALKDYVA R ILLN ^A M LLPDILPN T ^I LTE GYKLVAKA ^L DDKHHK T N FTDLKDVN V _G ^N _S ^{V S} _S V EITV ^I IYDAAEK GLKDLDLD V ^E K SHKLI NHVK ^I V _{S S} ELIVI DL ^R K GIL M ^T I SPEAFAVNAY LRD ^L Y _S LA QY ^I A QLRV KMD ^E KLK GKIYK VRELDI _Q ^S EHPH YDA LIKI AA MLATEK _G ^W R K _Q ^I FVHI ^KK TKEIF ALETNDLKLDD KVI ^Y VI _S ^L VTKIT D DDNP GEKDDIDLF V _C ^E _C ^E VV ^{F S} DTDL KL _C FYVIMD L _S ^K PDIEDK ^E _{C S} IKAPN S FVRLKT HHDKIE KN KILAEL YVWDL VLLPD _Q ^S _G ^S _Q R KL NLHEIL _S ^V HIYYKD H _Q ^S LDIM GY KTW _G ^I IN ^L E GL D FL _Q ^G H AAIAVDAPN ^V A GIY L ^P E N ^Y _G IRKKTTNNYNKNTY ^I Y QRAE ^L A G HFFR VI _G ^T TMKKTLE ^K A _G ^N _{G G} ND ^D KVK SVIKI KM VKKLKTVKNETK FIWFKYEDNT _G ^W Y KE STLYR LAK _Q AFFNWH _S ^G LE I _G ^W RK ^K IIL S IYDAKLYKA ^I A K NKVKK ^E K SIVRR PI PY RR ^E V GEN VLTP _Q ^{D K} R GEHIA T YF ^{N I} F _G D ^T I GT ^Y PDF N ^{L V} I _S ^N YI D _{S S} ^V TKFF THKYINAKVP _G ^{E L} K T _Q ^V NITKE DHH _Q ^C Y _Q PY ^F _{Q Q} FVAIP G ^L _G LI ^T R S P _{S G} TKFFVPNKLD ^V P _{G G} HN _Q ^S I _G ^T AIL ^S HVRYFV NAK ^L RNLLDY _G LIW _G ^P L _Q ^F L VYRPEK V _Q ^{L T} NPFE S YNE _Q ^S IDFDDE ERLK HRKDT K _G ^E _G ^{Y A} _G YNNNIE Q IMIWNE ^I _Q KDE ^I HID G HRE ^D _Q TMEI STEIKV ^L K GDLNEAID _S ^H TRI _G ^T KP DH ^{S S} EED _G ^I LKA E _S ^{L K} D QLDNKE _G ^T TKYPTYYV T EFKKNV AH VAFIET _S ^Q _S ^{A L} Y _{G S} K ^I EKF GH KR ^N N SL LE ^{N V} R S ^I Y SYKL _Q ^K _S ^{L D} IL QDENTTDH GLM _S ^{E A} NP SLLDF ^G N SV VK ^E F GI ^E AI ^E NTARLP NLFT SND _Q EEEI DY _G ^N YIDFDFLV ^P DT S YL _Q ^L FV ^L _{S Q} YK _S ^K YTTKK MLAFVT Y ^L A G ^{A I} L TL D KKPEKFEDDILP KA SE ^N V G EE _Q ^E K _S ^{E D} W SY RD RRKVYLFK _G ^L H ^{Y R} I G _Q W _G ^KL EV DPRFLFRKFRD _S ^T LYK _G ^L A ^G _{G S} T _Q ^{L Q} RIK S KKVLYKFK ENE ^N PR SKVTEN V ^L _G K SDD YEV _G ^K KPVLRKL KE ^L K QYTDFYKPDD ^I Y _G ^I D _S ^H LRI IETIEIY ^E ID KDF _Q ^F E T DEMDDATFFPLLKEAKMETMTRIR _C YT ^K NPD SETEILNAF IVTK ^K _S DN ELIV YKKLE ^G _{S S} V ^G TL ^I S KRMII K ^S VE WV NKPH YTVK DNFNV _S ^M KK ^F K _S ^I KF ARKDIYI ^P DYDA ⁰ K ^K K M _G ^V A _{Q S} ^Q LV ^K KVIE GPLLPA ^L D S MRNKDYL ^KL P LALVI ER ^K L _G A GIAT ^K _Q ND GEKKAFI ^N _S IKVI ^Y V GE QTNKILAE ₀ L _G F _G ^Y EMLPAMLLA N F _S ^G D _G ^R VDE ^E _{G S S} E ^{C T} _S KR N _S ^A RN KVW _Q ^KI N Q _S ^M TEVKD O M F L A D D T I L E H D M _S ^F E _Q ^L R I D N ^R IKN S E E Y I N K D L _S T K I ^Q Y G E N L N T ^S KAKIAE Q _S ^D D K E I M I E E A Y K K N L Y H M _G ^{N N Y} F G _G N ₆ ^W 0 ^{5 0} _{1 7} ^{. .} _{7 5} ⁷ 0 _{1 2 3 4 5} ⁹ ₉ 6 ⁶ ₁ ⁶ ₁ ⁶ ₁ ⁶ ₁ ⁸ 1 ₁ ¹ ₈

B ₇ ⁴

AIKL _S ^D F _G ^L KF _G ^D _Q ^R YAIKL _S ^D F _G ^L KF _G ^D _Q ^R YAIKL _S ^D F _G ^L KF _G ^D _Q ^R YAIKL _S ^D F _G ^L KF _G ^D _Q ^R YAIKL _S ^D F _G ^L KF _G ^D _Q ^R YAI YNKANNT KK ANNT KK KVYNKANNTKK KVYNKANNTKK KVYNKANNTKK KVYN TEV ^I KVYNK I KPV ^T RVI GKY ^I I _Q RTTEV SMALFKPV ^T RVI RTTEV RV GKY ^I I _Q ^I SMALFKPV _G ^T KY ^I I _Q ^I RTTEV RVI RTTEV RVI LKEVP ^S HHLLYLKEVP ^S HHLLYLKEVP ^S _S MALFKPV _G ^T KY ^I I _Q ^I LFKPV _G ^T KY ^I I _Q ^I RTTE QHHLLYLKEVP ^S _S MA QHHLLYLKEVP ^S _S MALFKP QHHLLYLK RH VL ^K _{Q S} H RALDERH VL ^K _{Q S} H RALDERH HRALDERH _S HRALDERH HRALDERH E ^E A ^I PI DLNEYE ^E A PI DLNEYE ^E VL _S ^K SA IDLNKYE ^E VL ^K SA IDLNEYE ^E VL _S ^K SA IDLNEYE E ^R _{S G} PN _S LL TADRLE ^R _{S G} PN _S ^I LF TADRLE _G ^R PN ^I P SLFTADRLE _G ^R PN ^I P SLFTADRLE _G ^R PN ^I P SLLTADRLE _G ^R IMVLEAT LEAT T LLN IMVLEAT LLN IMVLEAT LLN IM MVNY LA ^N LLN GYDL ^L IMV SMVNY LA ^N LLN GYDL ^L IMVLEA SMVNY LA _G ^N YDL _S ^L MVNY _G YDL _S ^L MVNY A _G ^N YDL _S ^L MV EK A _S ^K ED LIDKHEK A _S ^K ED LIDKHEK ^{K D} A _S EDLIDKHEK ^K LA ^N KHEK ^K L DLIDKHEK RV _S ^D DF VLDAKRV _S ^D DF VLDAKRV _S DF VLDAKRV ^D A _S EDLID SDF AKRV ^D A _S E SDF LVLDAKRV DL H ^N L GVKRYLPDL ^K H ^N L GVKRYLPDL H ^N L GVKRYLPDL ^N LVLD LPDL ^N VKRYLPDL EE _G ^K A _G ^G FLTLLEE _G A _G ^G FLTLLEE _G ^K A _G ^G FLTLLEE ^K H VKRY GA ^G _{G G} EFLTLLEE ^K H GA ^G _{G G} EFLTLLEE FDRH ^K E QKKDDEVFDRH ^K E QKKDDEVFDRH ^K E QKKDDEVFDRH ^K KKDDEVFDRH ^K KKDDEVFD LVNH _Q ^T L H _Q ^T L KLVNH _Q ^T L TVKYV ^{T K} A KLVN SK ^K E S ETVKYV ^{T K} A SK ^K E S ETVKYV ^{T K} A EKLVNH ^T _{Q Q} L EKLVNH ^T _{Q Q} L SK _S ^K ETVKYV ^T A S _S ^K K _S ^{K I} A EKLV LK NE ^E _{S G} T PD ^T NLK NE ^E _{S G} T PD ^T NLK NE ^E _{S G} TPD ^T NLK ^T ETVKYV _{S S} ^K K _S ^K GNLK KPD ^T ETV GNLK TV _S ^D NT V ^L _{G Q} DPTV _S ^D NT V ^L _{G Q} DPTV _S ^D NT V ^L _{G Q} DPTV ^D NE _G ^E TPD _G ^E SNT YV ^L DPTV ^D NE SNT YV ^L DPTV L IK ^A Y SRK _S ^T LMLL IK ^A Y SRK _S ^T LMLL IK ^A Y SRK _S ^T LMLL IK _S ^A RK ^T _{Q S} LMLL RIK _S ^A RK ^T _{Q S} LMLL V ^T R QTEKAKYDKKNV ^T R QTEKAKYDKKNV ^T R QTEKAKYDKKNV ^T R QTEKAKYDKKNV _Q ^T TEKANYDKKNV _Q ^T ILLRVLRDVAEKILLRVLRDVAEKILLRVLRDVAEKILLRVLRDAAEKILLRVL DAAEKIL D VIMD DLDLDD VIMD DLDLDD VIMDDLDLDD VIMDDLDLDD VVIM ^R _G DLDLDD E ^I V GKKNRI TKEIFE ^I V GKKNRI TKEIFE ^I V GKKNRITKEIFE ^I V GKKNRITKEIFE _G ^I KKNRITKEIFE _G ^I LKNY IKAPNLKNY IKAPNLKNY PNLKNY TIKAPNLK IKD ^V KT VRLKTIKD ^V KT IKAPNLKNY VRLKTIKD ^V KTIKA KTIKD ^V K TVRLKTIK DI ^F _{Q Q} P ^R T GD ALDIMDI ^F _Q VRLKTIKD ^V KT QP ^R T GD ALDIMDI ^F _{Q Q} P ^R T GDALDIMDI ^F _Q VRL QP ^R T GDALDIMDI ^F _Q P ^R _G DALDIMDI EA _S ^I F F NF REA _S ^I F NF EA _S ^I F NF FREA ^I _{Q S} F NPDD ^M NF SEY ^W HFFREA _S ^I GY D _S ^M EY ^W HFF GY ENPDD _S ^M EY ^W HFFR GY E DKLLK ^N KENPD KLLK ^N K IE KLLK ^N KENPDD _S ^M EY ^W HF GY KENPDD ^M N SE ^F HFFREA C _G ^W Y KENP E _G ^S KRVEF ^V I _S YIE STKFFE ^S D GKRVEF ^V I _S Y STKFFE ^S D GKRVEF ^V I _S YIE KLLK ^N IE DKLLK I _S ^N YIE STKFFE ^S D GKRVEF ^V I _S Y STKFFE _G ^S KRVEF _S ^V TKFFE _G ^S NALFKFANPFE FKFANPFE NPFE DLF R A ^S NAI ^S NAIFKFA ^S NAIFKFANPFE ^S NALFKFANPFE NA LN ^D V _S ^L P ^T YNE _Q DLF GKP ^D R _Q DLF SV ^L T SP ^T YNE GKP ^D R ^T YNE _Q DLF _Q DLF GKP ^D R Q ^A LN _S V ^L T SP ^T YNE GKP ^D R A YNE _Q ^S DL FA ^S _{S Q} VTY ET _S ^{Q A} LN SFA _Q ^S VTY IET _S ^{Q A} LN _S V ^L T SP SFA _Q ^S VTY IET _{S S} FA _Q ^S VTY IET _S ^{Q A} LN _S V ^{L S} _S P _G ^T KP SFA _Q VTY ^Q LN DIPLAK ^A I G DH A LAK _G ^A DH DH ^A IET _{S S} ^A FA KHV FPL Y _G ^{L A} DIP GKHV ^L A ^A DIPLAK _G ^{A L} A ^A DIPLAK _G ^A DH ^L A ^A DIPLAK _G DH A DEI _S ^K DLN _G ^L A _G ^G KDEI ^K FPL _G KHV SDLN ^L Y _{G G} A ^G KDEI ^K FPL SDLN ^L Y _{G G} KHV _G KHV ^A DI GA ^{G K} FPL KHHK V _S ^L DDKHHK KT ^L _G DKHHK KT ^L _G KDEI _S DLN ^L Y _{G G} A ^G KDEI ^K FPL SDLN ^L Y _G ^L GA ^G _G KH GKDE I ^L DL ^R KT GIL _S ^I ELIVI DL _G ^R IL ^I V _S D SELIVI L _G ^R IL ^I V _S DDKHHK KT ^L _G DKHHK KT ^L DDKH SELIVI L _G ^R IL ^I V _S D V _{S S} ELIVI L _G ^R IL ^I _S ELIVI I _S VTKIT YDA I _S ^L VTKIT YDA VI ^L D SVTKITYDA VI ^L D SVTKITYDA VI ^L D SVTKITYDA K ^D DIDLF KVI ^Y V GEK DIDLF KVI _G ^Y EK IDLFKVI _G ^Y EK IDLFKVI _G ^Y EK IDLFKVI ^Y VI _S ^L GEK ⁰ L _G YVWDL KILAEL _G ^D YVWDL KILAEL ^D D GYVWDLKILAEL ^D D GYVWDLKILAEL ^D D GYVWDLKILAEL _G ^D ₀ L ^{Q D} KVKH D ^{N N Y} FL VKH D FL KVKHD FL KVKHD FL RVKHD FL O D _{G S} V I R I M _{G G G} N D _G ^{Q D} K S V I R I M _G ^N _G ^N _G ^Y N D _G ^Q _S ^D V I R I M _G ^N _G ^N _G ^Y N D _G ^Q _S ^D V I R I M _G ^N _G ^N _G ^Y N D _G ^Q _S ^D V I R I M _G ^N _G ^N _G ^Y N D _G ^Q

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B ₇ ⁴

L R HVMI L NR ^{D R} NNIKKKLINR

F ^L N G KF _G ^{D R} N QYAIKL _S ^D F _G ^L KF _{G Q} YAVMIDF ^R NHIKKKLINR IKKKLINR QYAVMIDF ^R NN VMIDF KF ^D NHIKKK G _Q ^R YAVMID NT KK KVYNKANNTKK KVYIKLFM ^S KF _G ^D _Q YA I _Q KK KVYIKLFM _Q ^S KK VI I _Q RTTEV ^I KVYIKLFM ^S KF _G ^D QKK RTTNKA H I _Q ^I RTKNKA EH ^I KVYIKLF QRTTNKA Y ^{I I} I _Q RTKNKA S _S MALFKPV ^T RVI GKY _S MALFKEV ^S EH ^I I _Q ^I LFKEV ^S E GNI _S ^I MALFKEV ^S NI ^I I SMALFKEV ^{S K} _Q HHLLYLKEVP ^S HHLLYLPV ^T _G NI _S MA GRALHHLLYLPV _G ^T RALHHLLYLPV ^T _{G G} RALHHLLYLPV ^T _{G G} R SH RALDERH ^E VL ^K _{Q S} HRALDERKEVA RALDERKEVA TRALDERKEVA PI DLNEYE _S A PIDLNEYE VY ^K T Q DLNEYE ^K TRALDERKEVA LL TADRLE _G ^R PN _S ^I LLTADRLE _G ^H _S ^E A L _S ^S TADRLE _G ^{H E} VY _Q ^K SA ^S DLNEYE STADRLE _G ^{H E} VY _Q DLNEYE SA L _S ^S TADRLE ^{H E} VY G _S A AT LLN IMVLEAT N IMPN ^I L S L LLN IMPN _S ^I LN MPN _S ^I LA _G ^N YDL _S ^L MVNY ^N LLN N _S ^I GYDL ^L IMP SMVVLE ^D L GI ^N LL GYDL _S ^L MVVLE _G ^D I _G ^N YDL _S ^L MVVLE ^D L GI ^N L GYDL ^L I SMVVLE ED LIDKHEK ^K LA SEDLIDKHEKNYN LIDKHEKDYN NYN NL VLDVKRV ^D A SDF VLDAKKV AT _S ^R _Q ^S VLDAKKV T _S ^RS LIDKHEK QVLDAKKV ^R LIDKHEKDYN GV KRYLPDL ^N L KRYLPDL _S ^D DLNPKRYLPDL ^D A SDLNPKRYLPDL ^D AT _{S Q} ^S VLDAKKV AT SDLNPKRYLPDL _S ^D DL KE FLTLLEE ^K H GA ^G _G V G FLTLLEE H N FLTLLEE QK KDDEVFDRH ^K E KDDEVFD _G ^K A _G ^A N _G ^S KDDEVFD ^K H GA ^A N GN ^S FLTLLEE GKDDEVFD ^K H N FLTLLEE H GA _G ^A N _G ^S KDDEVFD _G ^K A _G ^A L ^T A EKLVNH ^T _Q K QL ^K A KLVRH AY KLVRH Y A EKLVRH Y E _{S S} ^K K _S ^K TVKYV _S ^I _S K ^K E S ETVNH _Q ^T MR ^K A SK ^K E S ETVNH ^T A QMR _S ^K K _S ^K NH ^T A QMR ^K A SK ^K EKLVRH S _G T PD ^T E L _G NLK E _G ^E KPD ^T NLKKYV PD ^T NLKKYV KPD ^T ETV GNLKKYV KPD ^T ETVNH _Q ^T KKYV AY V TV ^D N SNT YV ^L _{G Q} DPTV NE ^V K SRV ^L _{G Q} DPTV RV ^L DPTV _S RV ^L _G NL QD SR K ^T _Q DP SLMLL RIK _S ^A RK _S ^T LMLL ^D NTAPK _S ^T LMLL ^D NE _S ^V SNTAPK ^T _{Q S} LMLL ^D NE ^V PTV SNTAPK _S ^T LMLL ^D NE AK YDKKNV _Q ^T TEKANYDKKNV ^S _{S Q} RIKLIYDKKNV _Q ^S RIKLIYDKKNV _Q ^S RIKLIYDKKNV ^S _S NT QRIK LR DVAEKILLRVL AAEKILTEKMTDAAEKILTEKMTDAAEKILTEKMTDAAEKILTEK MD DLDLDD VVIM ^R D GDLDLDD RVR DLDLDD RVR LRVR DLDD RI TKEIFE _G ^I KKNRITKEIFE ^I L GIVIR _G ^T TKEIFE ^I L GVVIR ^T DLDLDD GTKEIFE _G ^I VVIR ^T DL GTKEIFE ^I LRV GVVI KT IKAPNLKNY KAPNLKKKN IKAPNLKKKN LIKAPNLKKKN LIKAPNLKKKN RT VRLKTIKD ^V KTI Q TVRLKTIKNY ^T L TIKNY ^T FVRLKTIKNY ^T FVRLKTIKNY GD ALDIMDI ^F P _G ^R DALDIMDID ^V _G FVRLK MDID ^V _G KALDIMDID ^V _G NF HFFREA ^I _{Q S} F HFFREA ^F _Q NKALDI QPEF REA ^F _Q N QPEF HFFREA ^F _Q NKALDIMDID ^V EY _G ^W Y KENPDD ^M NF SEY _G ^W Y KENP _S ^I F FD ^W HFF GY ENP _S ^I F FD _G ^W Y KENP ^I _Q PEF ^W HFFREA ^F _{Q Q} P SF D _G Y KENP _S ^I F LK I _S ^N YIE DKLLK I _S ^N YIE D _S ^M EA ^N K IE D _S ^M EA I _S ^N YIE DD ^M F SEA I _S ^N YIE EF _S ^V TKFFE _G ^S KRVEF _S ^V TKFFE ^S D GDKLFP ^V I _S Y STKFFE ^S D GDKLFP _S ^V TKFFE _G ^S DKLFP _S ^V TKFFE ^S DD _S ^M GDKL FA NPFE ^S NAIFKFANPFE NAKRV NPFE ^S NAKRV NPFE NAKRV ANPFE AKRV LA YNE _Q DLF R A YNE _Q ^S DLIFK ^L A S _Q DLIFK ^L A S _S P _G ^T KP LN ^D V _S ^L P _G ^T KP LNF ^T YNE ^T YNE _Q ^S DLIFK _S ^L E ^S N QDLIFK ALNF _G KP F ^G YN Y IET _S ^Q _S ^A FA ^S _{S Q} VTY ET _S ^Q _S ^A FA ^D RY _S ^G _G KP S _S VKAIET _S ^Q _S FA ^D RY _S ^{G D} RY _{S G} ^T KP ^Q LNF K _G ^A DH DIPLAK ^A I GDH A D _Q VTPTDH ^S _S VKAIET ^Q LN S _S ^A FA ^{A S} _S VKAIET _{S S} FA ^D R PL ^L A G ^A KHV FPL Y _G ^{L A} K _Q ^I PLALL ^L A ^A D VTPTDH ^L A ^I _Q VTPTDH A ^S _S V GK ^I _{Q Q} PLALL ^A D PLALL Y _G ^{L A} D ^I _Q VT LN ^L Y GA ^G _G DEI _S ^K DLN _G ^L A ^G _{G G G} K _{Q G} KDEV ^L Y _G KDEV ^L Y GA ^G _G KDEV FKT _G ^L A ^G _G K _Q PLA GKDEV KT ^L _G K SDDKHHK V _S ^L DDKHI ^K FKT _G A ^G SD ^L _G DKHI ^K FKT SD I _S ^K D L V _S ^L DDKHI ^K F SD IL ^I V SELIVI DL ^R KT GIL _S ^I ELIVI HK ^I L ^I V _S D VI K ^I L _S DDKH CL ^I V ^L SELIVI HK ^I L _S ^I ELIVI HK IT YDA I _S ^L VTKITYDA I _S ^L DL ^R _C L _S ELI GKNYDA VI ^L H SDL _G ^R KNYDA DL ^R _{C G} KNYDA VI _S ^L DL ^R LF KVI ^Y V GEK DIDLFKVI ^Y V GEK VTKDIKVI ^Y _{G G} EK TKDIKVI ^Y VI _S ^L GEK VTKDIKVI _G ^Y EK VTK ⁰ DL KILAEL _G ^D YVWDLKILAEL _G ^H DID KILAEL ^H V GDIN KILAEL _G ^H DID VKILAEL _G ^H DID ₀ KH D ^{N Y} FL VKHD ^N L YVW ^I V Q D W ^I V Q D FL YVW _Q ^I O K I M _G ^N _{G G} N D _G ^{Q D} K S V I R I M _{G G} ^{N Y} F G N D _G ^Q D K V V _S ^S M _G ^{N N Y} FL V G _G N D ^Q Y G D K V V _S ^S M _G ^N _G ^N _G ^Y N D _G ^Q D K V V ^S D S M _G ^N _G ^{N Y} FL ^Q YVW G N D _G D K V ₆ ^W

0 ^{5 0} _{1 7} ^{. .} _{7 5} ⁷ 1 _{2 3 4 5} ⁹ ₉ 8 ₁ ⁸ ₁ ⁸ ₁ ⁸ ₁ ⁸

1 ¹ ₈

B ₇ ⁴

LI NR ^{N R} NNIKKKLINR ^R NHIKKKYYNR

F F _{G Q} YAVMIDF KF _G ^D _Q YAVMI L ^R NHVMI IKKKYYNR QYAIKL ^D L SF ^L NR GKF _G ^{D R} NN QYAVMI L KF ^{D R} NNIKKK G _Q YAVMI M ^S K Q KK KVYIKLFM _Q ^S KK KVYNKANNTKK KVYIKL _S ^D F _G ^L KK EH I _Q ^I RTKNKA ^I KVYIKL _S ^D F ^L KF _G ^D GKK L _S ^D RTTEV RVI _Q RTKNKANNT ^I KVYIK QRTKNKAN NI _S ^I MALFKEV ^S EH ^I I _Q RTTNKANNT SMALFKEV ^I I _Q ^I LFKPV _G ^T KY ^I I ^I EV VI ^I I GMALFKEV AL HHLLYLPV ^T _G NI GRALHHLLYLPV ^T RVI _G MA GKY HHLLYLKEVP ^S _G MALFK QHHLLYLPV ^T R GKY LLYLPV ^T R GK KT RALDERKEVA RALDERKEVP ^S RALDERH HRALDERKEVP ^S HH Q LNEYE VY ^K T Q DLNEYE ^{H E} VL ^K _{Q S} HDLNEYE ^E VL _S ^K SA IDLNEYE ^K _Q RALDERKEVP L ^S D S TADRLE _G ^H _S ^E A L _S ^S TADRLE _{G S} A PITADRLE _G ^R PN ^I P SLLTADRLE _G ^{H E} VL _S HDLNEYE SA PITADRLE ^H VL G _S ^E A DL LLN IMPN _S ^I N IMVLEAT LLN IMPN _S ^I LL LN MPN _S ^I GI _G ^N YDL _S ^L MVVLE ^D L GI ^N LLN N _S ^I LL GYDL ^L IMP S VVLEAT ^N LL GYDL _S ^L MVNY A _G ^N YDL _S ^L MVVLEAT ^N L GYDL ^L I SMVVLE R IDKHEKNYN LIDKH _G ^M KNY LA KHEK ^K L DLIDKHEKNY S ^S L Q VLDAKKV T _S ^R _Q ^S VLDVKRV A _S ^K ED ^L ID GLDAKRV ^D A _S E SDF LVLDAKKV ^K LALIDKHEKNY NP KRYLPDL ^D A SDLNPKRYLPDL _S ^D DF KRYLPDL ^N VKRYLPDL ^D A _S EDVLDAKKV A _S ^K SDF N LTLLEE FLTLLEE H ^N L GVLLTLLEE ^K H GA ^G _{G G} ELLTLLEE ^N LKRYLPDL _S ^D DF N ^S F G KDDEVFD ^K H GA ^A N GN _G ^S KDDEVFD _G ^K A _G ^G KDDEVFDRH ^K KKDDEVFD ^K H _G VLLTLLEE H GA _G ^G DEVFD _G ^K A _G ^G AY A ^K EKLVRH KLVNH ^T _{Q Q} L RH ^K EKD K MR _S ^K K _S TVNH ^T AY QMR ^K A KLVRH ^K E QK SK ^K E S ETINH _Q ^T L ^K V SK ^K E S ETVKYV ^T V EKLV S _S ^K K _S ^K NH ^T _{Q Q} L ^K V ^K EKLVRH S VK PD ^T E LKKYV KPD ^T NLKKYV ^T PD ^T NLK TPD ^T ETI ^T GNLKKYV ^I _S K SPD ^T ETINH _{Q S} R V ^L _G N TV E _S ^V RV ^L _{G Q} DPTV NE ^E _{S G} TV ^L _{G Q} DPTV ^D NE _G ^E SNT YV ^L DPTV ^L _G NLKKYV AP K ^T _Q DP SLMLL ^D N SNTAPK _S ^T LMLL ^D NT K _S ^T LMLL RIK _S ^A RK ^T _{Q S} LMLL ^D NE _G ^E KV _Q DPTV SNT YK _S ^T LMLL ^D NE LI YDKKNV _Q ^S RIKLIYDKKNV ^T _{S Q} RIK ^A Y SRYDKKNV _Q ^T TEKAKYDKKNV _Q ^T RIK _S ^A RYDKKNV ^T _S NT QRIK MT DAAEKILTEKMTDAAEKILTEKAKDAAEKILLRVLRDAAEKILTEKANDAAEKILTEK R LDLDD LRVR LDLDD RVLRDLDLDD VIMDDLDLDD LRVLRDLDLDD R ^T D G TKEIFE _G ^I VVIR ^T D GTKEIFE ^I L GVVIMDTKEIFE ^I V GKKNRITKEIFE _G ^I VVIMETKEIFE ^I LRV GVVI TL IKAPNLKKKN KAPNLKKKNRIIKAPNLKNY TIKAPNLKKKNRIIKAPNLKKKN GF VRLKTIKNY ^T LI RLKTIKNY TIKD ^V K TVRLKTIKNY TVRLKTIKNY NK ALDIMDID ^V _G FV QNKALDIMDID ^V KTVRLK MDI ^F _{Q Q} P _G ^R DALDIMDID ^V K EF HFFREA ^F PEF HFFREA ^F _Q ALDI QP ^R T GD REA _S ^I F NF HFFREA ^F _Q TALDIMDID ^V FD _G ^W Y KENP ^I _{Q S} F Y KENP _S ^I F NF ^W HFF GY ENPDD _S ^M EY _G ^W Y KENP ^I _Q P _G ^R D HFFREA ^F _{Q Q} P SF F _G ^W Y KENP _S ^I F EA I _S ^N YIE DD ^M FD _G ^W SEA I _S ^N YIE D _S ^M EY ^N K IE KLLK I _S ^N YIE DD ^M N SEY I _S ^N YIE FP _S ^V TKFFE _G ^S DKLFP _S ^V TKFFE ^S D GDKLLK ^V I _S Y STKFFE ^S D GKRVEF _S ^V TKFFE _G ^S DKLLK _S ^V TKFFE ^S DD _S ^M GDKL LA NPFE NAKRV ANPFE ^S NAKRVEFNPFE N S ^T YNE _Q ^S DLIFK _S ^L YNE _Q DLIFKFA ^S NALFKFANPFE NAKRVEFNPFE AKRV QDLF _Q DLLFK Y _S ^G _G KP LNF RY _S ^G _G ^T KP LNF ^T YNE ^D R SV ^L A DLLFKFA YNE ^S SP ^T YNE _Q ^S GKP F KA IET _S ^Q _S ^A FA ^D VKAIET _S ^Q _S ^A FA ^D R _G KP SV ^L A SPIET _S ^{Q A} LN SFA _Q ^S VTY IET ^Q LN ^T KP S _S ^A FA ^D R A _G ^Q LNF PT DH D ^S _S I _Q VTPTDH A D _Q ^S VTY DH ^S _S V _S ^L PIET _{S S} ^A FA ^D R LL ^L A G ^A K _Q PLALL Y _G ^{L A} K _Q ^I PLAK _G ^{A L} A ^A DIPLAK _G ^A DH ^L A _Q VTY A ^S _S V GKHV _G ^A D PLAK ^A DH G Y _G ^{L A} D ^I _Q VT KT ^L Y GA ^G _G L _G KDEV FKT _G ^L A ^G _{G G} KDEV ^L Y _G KDEI ^K FPL SDLN ^L Y GA ^G _G K _Q ^I GKDEV FPL _G ^L A ^G _G K _Q PLA GKDEV IL _S DDKHI _S ^K D ^I V _S ^L DDKHI ^K FPL _G A ^G SDLN ^L _G DKHHK KT I _S ^K DLN V _S ^L DDKHI ^K F SD CL ^I V SELIVI HK ^I L ELIVI HK ^I V _S D VI L _G ^R IL ^I V _S ^L DDKH SELIVI HK T _S ^I ELIVI HK KN YDA I ^L _C L _{S S} DL ^R _G KNYDA I _S ^L DL ^R KT _S ELI GILYDA VI ^L D SVTKITYDA DL ^R K GILYDA VI _S ^L DL ^R DI KVI ^Y V GEK VTKDIKVI ^Y V GEK VTKITKVI ^Y _{G G} EK IDLFKVI ^Y VI _S ^L GEK ^H VTKITKVI _G ^Y EK VTK ⁰ V KILAEL _G ^H DID VKILAEL _G ^H DIDLFKILAEL ^D D GYVWDLKILAEL _G DIDLFKILAEL _G ^H DID _{0 Q} ^{I S} D ^{N N} FL ^Q YVW _Q ^{I N} L YVWDLD FL RVKHD FL YVWDLD O V _S M _{G G G} ^Y N D _G D K V V ^S D S M _{G G} ^{N Y} F G N D _G ^Q D K V K H M _G ^N _G ^N _G ^Y N D _G ^Q _S ^D V I R I M _G ^N _G ^N _G ^Y N D _G ^Q D K V K H M _G ^N _G ^{N Y} FL ^Q YVW G N D _G D K V ₆ ^W

0 ^{5 0} _{1 7} ^{. .} _{7 5} ⁷ 6 _{7 8 9 0} ⁹ ₉ 8 ₁ ⁸ ₁ ⁸ ₁ ⁹ ₁ ⁸

1 ¹ ₈

B ₇ ⁴

YY NR ^{D R} NHVMI L NR NHVMI

L F _{G Q} YAIKL _S ^D F _G ^L KF _G ^D _Q ^R YAIKL ^D L SF ^L NR GKF _G ^{D R} N _S IKLDV NRYFELI PIF NR QYYIMLFY KYDTNVN _S ^H AF ^D L _S MVVLE GKHEKNY F ^L K G KK KVYNKANNTKK KV EL E KK KRLI ^D KF S KKIAKRV A _S ^K NT I _Q ^I RTTEV ^I KVYNKANNTKKI RT ^K N QAHA _G ^G R I ^{D R} FT I _{S Q} IEPMKVI VI _S MALFKPV ^T RVI GKY ^I I _Q RTTEV RVIII SMALFKPV _G ^T KY LFLPV YH K _C ^L TKMYARPTF ^I I SI ^Q LPDL _S ^D DF GLLEE H Y ^S HHLLYLKEVP ^S HHLLYLKEVP ^S M _G ^E Q _Q ^S HLFT V _G ^N KE KHKLFP K _Q RALDERH VL ^K _{Q S} HRALDERH _S HKA DE ^R N Q EVKP RAEL ^K KYYD KHLEVFD _G ^K A _G ^G GVKAF RALEKLVRH SH DLNEYE ^E A PIDLNEYE ^E VL ^K A IDL _G ^L EYR _G ^H IVKVI NLE KTINH _Q ^T PI TADRLE ^R _{S G} PN _S ^I LLTADRLE ^R _{S G} PN ^I P SLLTAERLIM ^I VPE SANY ^N ILY ^R K Q _S ALIY _Q ^L LL ^N LLN IMVLEAT D ^L MVPNWN DLEEIE ^I LLLD TAD _G ^A NLKEYV GPLPN LDPTV AT _G YDL _S ^L MVNY LA ^N LLN LEAT LL GYDL ^L IMV SMVNY A _G ^N YDI _S EKVL D IDT ^N L DM ^V NE LA LIDKHEK A _S ^K EDLIDKHEK A ^K L SEDLVEKHRVDY ^Y K SE ^G YNLLR IPM _G ^{S F} _G Y G LIDK ^L L QV ^T _S NT QRIK ED VLDVKRV _S ^D DF VLDVKRV _S ^D DF LVLEDKDL ^E _Q VLD G LDI ^S I QMEAAYE VLDEEILTDK NL KRYLPDL H ^N L GVKRYLPDL H _G ^N VKRYLPEE ^D AN SDK _Q ^I L _S ^I REKKEENV K KRYLDD GV FLTLLEE _G ^K A _G ^G FLTLLEE _G ^K A _G ^G EMLTFLFD ^K HT ^K MIEEPRVD ^G H FLTIFE ^I LRV GVVI KE KDDEVFDRH ^K E KDDEVFDRH _Q ^K KKDD QK A ^K EKLVNH ^T _Q K QL L ^D VLV _G AK _S ^Y _S KD MLDIL ^V _{G G} YA KDDPNLKKKN GKTIRHRHLR ^Y K NKN L ^{K K} A KLVNH _Q ^{T I} _S K _S TVKYV ^T _S K ^K E S ETVKYV ^T KA SAK _S ^{K S} ELKNHPYDA ^A _{C Q} D ^I VE SKFI _G ^K LLV ^K A SK ^K KTIKNY SIMDID ^{V E} _S PD ^T E LK E ^E _{S G} TPD ^T NLK NE _G ^E TP _G E KYILIVER GK V ^L _G N T _Q DPTV ^D N SNT V ^L _{G Q} DPTV _S ^D NT V _S ^Q _Q ^F NP ^T V Q ^S RYPY PE LRL ^Q EI SKT _Q NADD V ^L FREA ^L _{Q Q} P QKENP _S ^I FM AY K _S LMLL RIK ^A Y SRK _S ^T LMLL IK ^A Y SRKIL LI _Q ^{S D} DL SNKTTR ^K T SFEPLWVD ^P SR YDKKNV _Q ^T TEKAKYDKKNV ^T R QTEKAKYDK _Q ^I YILRI EYNNELI ^F K _S LYIE AN EVAEKILLRVLREVAEKILLRVLRDAALLD TE ^D T SFYDAL ^I KH _S ^L _S YDKFFE ^S DDA GDKL G LR DLDLDD VVIMDDLDLDD VIMDDLDLDE _G ^I LR ^L YK ^S AAV DAAE AKRV ME TKEIFE _G ^I KKNRITKEIFE ^I V GKKNRITH ^L DLK _G TIK _S HKK DLD ^S N RI IKAPNLKNY IKAPNLKNY ^I NIKVV _G ^E _Q ^R _G TDMA IKVHRH TKE ^E _Q DLIFK Q DF S _G LTKRKKPTLHEL _Q ^D EVLHPNLIKTT ^A L SFA ^D R KT VRLKTIKD ^V KT Q TVRLKTIKD ^V KTVK ^E KTKINYPIIVREENEAVHIIRVRLA ^S _S V RT ALDIMDI ^F P _G ^R DALDIMDI ^F _Q VR QP ^R T GDAL _Q ^L LMEADLLV KNLE LDL ^A D GK ^I _Q VT QPLA GD HFFREA ^I _{Q S} F YRNP ^S ALETTFP Q HLRMM NIKD ^E A G HFKKDEV NF _G ^W Y KENPDD ^M NF SEY ^W HFFREA _S ^I F NF GY ENPDD _S ^M EY ^W HF GYNKTA ^L E SF ^I L SEH _G ^W YDLRT _G ^S DEEYD _G ^W Y TDKHI ^K F SD EY ^V I _S ^N YIE DKLLK I ^N K SYIE KLLK IK _G ^S NEE I IFFETP LK _S TKFFE _G ^S KRVEF _S ^V TKFFE ^S D GKRVEF ^V ITY STKFFDPDK ^N L _S ^V TTKIMI ^L RPHW I _S ^N TVI SVNRL _S ^V TKRVI ^L HKK SDLE EF NPFE NALFKFANPFE FKFANPFEKDLKR ^K _{G S} TNPKYFDANKAAKNPFKEKDVTK FA ^{S T} YNE _Q DLF R ^L A YNE ^S NAL QDLF ELDIFF _Q ^K A FEPKDY HR ^T YNREL LA _G KP LN ^D V _S P _G ^T KP ^D R SV ^L A SP ^T FN GD ^D SP IET _S ^Q _S ^A FA ^S _{S Q} VTY ET _S ^{Q A} LN SFA _Q ^S VTY ID ^P _{Q Q} K ^A F N _G ^{T Y} K QFDID ^V VI _S ^K YV _G NPHFL ^G DIN QYVW AI _S ^F H SV ^{N G} L IDNLEIRTKND Y ^A DH A DIPLAK _G DH A LAK _G ^A DH ^V KKV ^A _{S G} E QV ^L IRN CDH ^E _Q ^A D _{Q S} LD ^D KV K _G Y _G ^{L A} KHV FPL Y _G ^{L A} DIP G _G KHV ^L _G EDNPL ^T R Q E Y _Q ^A TNLL ^F FILVDH S TTR Y ^L _{S S} VV G ^I WH ^G GPY PL _G ^L A ^G _G DEI _S ^K DLN _G ^L A _G KDEI ^K FPL SDLN ^L Y _{G G} K KLAI E _S ^A T _G ^L N AETLR _Q ^M EVR _G ^L AL ^V LE R _G ^E LN ^L _G K SDDKHHK V _S ^L DDKHHK KT ^L N DIII _S ^N EA PRKLE VA ^I T R GI ^T _{Q G} ANIT KT ^I V SELIVI DL ^R KT GIL _S ^I ELIVI L _G ^R IL ^I V _S E SELILKDHKTL ^V IK _G ^N STEV ^K KDV GD IFYNY _S ^I ELVA IL YDA I _S ^L VTKITYDA VI ^L D SVTKITYAA IRDDLKLTY KV _Q ^M _S ^N I FE ^L KIP IT KVI ^Y V GEK DIDLFKVI _G ^Y EK IDLF DLVITKRYE ^E M SLVV H _S ^{Q L} YDA GKAI ^Y E _S EDK _G ^E G AILDN ⁰ LF KILAEL _G ^D YVWDLKILAEL ^D D GYVWDL ^K AI _G ^Y QILADD IVRRKLK ^D DT ^G P GLTKLIA _S ^E NE ₀ DL D ^N L VKHD ^N L KVKHD FH ^D D G IIRKETL ^Y E _{S S} ^D GALMIL ^E NT KE O K H M _G ^N _G ^Y F G N D _G ^{Q D} K S V I K I M _{G G} ^{N Y} F G N D _G ^Q _S ^{D N N} KFE _Q V I K I M _{G G G} ^Y N Y I _Q ^Y K N K R M A F A F K I D T ^K I Q L ^V E S M _G ^N _G ^{N Y} _G R R K D D I ₆ ^W

0 ^{5 0} _{1 7} ^{. .} _{7 5} ⁷ 1 _{2 3 4 5} ⁹ ₉ 9 ₁ ⁹ ₁ ⁹ ₁ ⁹ ₁ ⁸

1 ¹ ₈

B ₇ ⁴

LL KY _{G Q} YYIPN F _{G Q} YYIPN _G KKIKV _{Q S} V _S EHKKIKVDVVALV ^S KKIKVDVVALV ET KKVKV ^K _G LK KIKV L _S ^{K A} II AAE _S ^L AE II A V I _Q II A V ^I I _Q ^S NAII RT ^K NVL _S TK QDDYF _Q ^K I RA _Q ^KN V QDYF ^K _{S Q} LFM ^Q R GLFLPPN ^N I GLFM ^Q R GLF _Q ^{Y I} E S ^L V _S ^I EHFM ^Q R GLF _Q ^{Y I} E S V _S EH AD YM _G ^K LFLP ^A I M _G ^K LFLP A LARHLFT EVL _S ^K HHLFTAE _S AE RHLFTAE _S ^I AE KL KHLFTRN ^D A SD ^G L _S Y GE HLFTRN _S ^D D _G ^G EEKALDE _Q ^R YF ^K T QAKALDELPPN ^N I CLKALDELPPN ^N I GL QVKALDEE ^L K ALDEE YK ^H N G A LNDLNEY AVL _S ^K DLNEY TVL _S ^K LE DLEDYH _G ^{D K} H GA ^T T _C K Q EDLEEYH _G ^{H K} H GA ^T TTDLNE Q TAERLIM _S ^D D _G ^G ELTAERL _Q ^R ET TAERVIMRHA _S ^A KTAERVIMRHV _S ^A _S ^{T H} NYF ^K T QATAERL _Q ^R TV ^L MV H KI A LN ^H NYF ^K T QA NLLE MVNHEA LLE MVNHEAK ^N LLE GYDI _S EK _G ^K A _Q ^{T N} LLE GYDI ^L K _{G S} IM _S ^D D _G ^G EL ^N LLE H _G YDI ^L K _G ^D A LN SIM _S D _G ^G EL A YDI _S DKKYVL _S ^T _G ^N YDI _S ^Y DKKYVLYLIEKHRVRHV _S ^A _S ^E LIEKHMV H KILIEKHMV H KI S ^T _{G Q} LVEKHRVADKLTLVEKHRVADKLRVLDEKDLNHEAVVLDDKEK _G ^K A _Q ^T VLDEKEK _G ^K A _Q ^T AY VLEDKDL KRYVLDDKDL KRLKRYLPEEDYRLTKRYLPRVRHV _S ^A _S ^E KRYLPRVRHV _S ^A _S ^E LRKRYLPEE ^S N SIVRRKRYLPEE ^S N SIVRNMLTFLFDKDKMTMLTFLDLNHEAVMLTFLDLNHEAV ML MLTFLFDTEIRKMLTFLFDTEIR DDYVIV NKRYKDDYVEEDYRLTKDDYVEEDYRLT RRKDDYVLVLRN DD LVLRN ^S K R TL _S ^L IVRR DKLT KFDKDKLT R ^G KA ^K TIVV ^G RK V ^Y V QKTIVV ^G _Q T DK LKTEI ^K T KFDK SK ^R D S EIV NKRY ^K T SK ^K D S EIV NKRY R _Q AK _S ^D K SELKKK ^V _G PK QEIAK ^K _{S S} LKRK ^V _G K _S ^K K QEVPE ^A E TILRN ^R K GRPE ^A ETI _S ^S IVRRPE ^T ETI _S ^L IVRR GKPE TVNYPFKPE ^G E H VI V ^F _{G Q} EPLKTEI V ^F _{G Q} EPLKTEI NVV ^F DE L DF ^F _G ETVNYPFDV ^F _G E K _Q EP V _Q ^S RK ^V ND QKVK _S ^K LFLTILRN ^R K GRK _S ^K LFLTILRN ^R K GR ED K ^Q _Q DP SLILV _Q ^{S Y} E SF ^E V GK ^P _Q NPL DF SLKLV _Q ^{S Y} ELK _S LFL SFKYDP ILNYPLDYDP YH V NDYDP YH V ND LL YDKKYIL ^I K SFL LYDK IL ^I K SFL LDAA ^K Y SLN ^I DL ^L E DAA _S ^K LV ^S V QRK _Q ^V EVDAA _S ^K LV ^S V QRK _Q ^V EI ED DAATLD NEV _S ^L FDAA ^E Y SLD NEV _S ^L FD E _{G S} F _G ^K D KLDILNYPLDD KLDILNYPLD FL DLDLDE _G ^I DKKYNDLDIDE _G ^I DKKYKT ^L KLD QELYLK ^L R SFL FT _Q ^L ELYN L E T _Q ^L YN L E LF TY INIKKRRKFTH IKKRRKFIKENNIKDEV _S ^L FIKENNE ^I D G E _S ^L F _G ^K IK ^E L GNNE ^I D G R _S ^Y F _G ^K ST IK _S ^E TLIKIFVPDIK _S ^{E I} N SL VP RLKTEIDKKYK RLKTLK _S ^L FL TLK _S ^L FL Y RLKT RLKT ^I KIF QIF IL ^A V GALDIMEAKRKKF _S ^V LDIMIKDEV ^L F SF ^V RLK SLDIMIKDEV ^L F SF K ^F V G ALKLM ^Q IF ILAV GA ^Q DKPALKLMEA ^Q NKP HFYKNPIFIPA HFYKAIDKKYK KEIDKKYK P HFYRNP ^A _{S Q} VFI ^W HFHRNP ^A _{S Q} VFI ^W YHKNN F T A _G ^W YHKNEAKRKKF ^W HFY GYHKNEAKRKKF L _S ^G _G ^W YNKTT PLDL _G ^A _G YNKTT PLDL ^A _{G G} P _G ^{S N} A _C ^L P IKYINPIFIPA K ITYIK _G ^S I ITYIK _G ^S I ^V IKYI S ^R K TK DP ^A _{S Q} VFL ^V TKFFK F ^V IKYINPIFIPA F _G ^A _S ^V TKFFDPI _S ^{N K} KL QDA _S ^V TKFFDPI _{S Q} D ^F _{S S} NPF _S ^F _S ^F DLPLDI ^A _{S G} NPFTDA _G ^{S N} T _S TKFF A ^L A CPNPFAD _S ^KS F G ^N T SA ^L A CP I NPFEKDLHKK ^E TNPFIKDLHKK ^E I M V KNL FL EDP _Q ^A VFL L _S ^F N LDDLN _Q L FN F _G ^{T F} D Q ^E E QAF _Q ^E I _S ^N EEA _G ^{T F} D DP ^A _{S Q} V Q ^E E QADLPLDI _G ^{A T} D G _Q ^{F E} ADLPLDI _G ^A ET ^T F G ^D E ^D ELDDLN _Q K ^P _Q ^AF HITWVT _G ^T EVHKKKTIK _Q ^A T M I KNLIK ^A _{Q Q} T KY I _{Q Q} K _{S S} VDIVNLI ^E _Q ^AF HITWVKIK _Q ^A T Q _Q ^P K _{S S} VDIVNLDH T _S ^S K DLNRFDH T _S ^S F _Q ^E I _S ^N EEADH ^S M SF ^E V QI ^N KNL SEEA KKDH ^{N V} VYVVHLDH KVYVVHL Y _G D _Q ^V ITWVT Y _G ^N AVHKK T ^N T AEVHKKKT IL ^L KK G _G EDA K Y _G ^{L V} K GEDA KKDIANL _G ^L KV ^K A GKK DLN _C ^K F ^L Y _{G G} EV _G ^K KK LNRF D ^L Y GALNKLE _S ^D V _G ^{E Y} N GI _G ^L TLNKLE ^D K L _S V ^E N _G ^L EV ^K A GK G _G ^Y I KIDDIVYIIHL KIDDD _Q ^V ITWVT KIDDD ^V D QITWVT K _S ^I DADDIILDDK DAEDIILDDK ^I ELIVID ELIVKK ANL _S ^I ELIVKKDIANL YV _S ELIVKDRRAK _S ^F _S ^I ELIVKDHRAK ^F _{S S} YEK KD ^S K ^I SV ^E _G ^Y N _{S G} IYEK IV ^D I CIIHLYEK IVYIIHL G A ^Y VKDDINE YEA KDDINE IL ^Y I F ^Y E _G ELT TK AL ^Y I GEID K _{S S} AI _G ELVIVTL _S ^A TAV ^Y V GELVIVTL ^E N SKLFAEL ^L T QRDN ^F N SKLFAEKN ^S K SV ^{E Y} NNAL ^Y I GEID K G _G IKLFAEKD _S ^S V _G ^{E Y} N GI ⁰ A KKLADD ^F IKKLADD DKE LNT D _G ^K NN T LT TK T LT TK ₀ E _S ^N E ^D DKE N FH _G LDI _S EE _S ^F A _S ^{E Y} F GNHVIK ^K ENN SLAEA _S ^{E Y} F GNL ^L T QRDN ^F N H _G ^D LDI _S EA _S ^{E Y} F GNL ^L T RDN _S ^F O L L M ^N _{Q G G G} ^Y N Y V E N D V E M _G ^N _G ^{N Y} F G N Y V E N D V ^S E S M F F D W Y V D K Y F L M F F D W D _G ^K N N K E N M F F D W D _G ^K N N K E N ₆ ^W

0 ^{5 0} _{1 7} ^{. .} _{7 5} ⁷ 6 _{7 8 9 0} ⁹ ₉ 9 ₁ ⁹ ₁ ⁹ ₁ ⁹ ₁ ⁰ ₁ ⁸

2 ¹ ₈

B ₇ ⁴

W DTKVRKAH L YFLIE Y _Q ^L IVADE W ^L ADE W ANY _Q ^L IVADE F ^H V GDFL ^{H E} VMLVA L _G ETE I _S ^F K ^P K W SE F ^H ANY GL TADVF ^H ANY _Q IV GL LTADVF NRATE _S IKLNM NR RV ^P F R _Q ^{E P} F _G ^H L LTADVF ^P KYY NKA I KF ^D N _S ^D IKLDV NR ^E L Q _{G Q} ^R YYIMLFY KY _G ^I A _S ^L IL _S ^D _C ^VG _Q N G KY _G ^I A ^L RV SIL _S ^{D V} _Q NR ^E C _G ^G KY ^I _{Q G} A ^L RV SIL _S ^D _C ^VG _{Q G} KKE ^R NL QYRTVT _S ^P VKV NEL E KKEIH LI KV PVAD ^E KK S II ^R E Y _Q ^H KKEIH E NY _Q ^H KKEIH E ^{H D} RT _Q ^K AHA _G ^G R IVLKK _Q D ^K N GL VLKK _Q ^R D ^{K R} _{Q G} L E IVLKK _Q D ^K NY GL YI _G RT _S ^D AEVF _G ^E LFLPV H KIDEPRVRY ^K E I QV KIDEPRVRY _Q ^K V KIDEPRVRY ^K E QV NHILYF ^F LFA NV ^N Y GKE KHELLDINAPY KHELLDINAPY KHELLDINAPY KA FK ^Y _G ^S M K ^V _Q H G _{S G G} ^G _Q P KAEF EKEDDA KAEFVEKEDDA KAEFVEKEDDA EL _G ^E DE _S ^K MPNY ^S KA Q DL ^F DE ^R V GEYR ^H EVK G VPE EL FLT L YKFLT EL KFLT TALEY IVLKH TAERLIM _S ^I ADY TA ^Y YK SE I ^{Q L L} E G _S TA _S ^Y E I ^Q _{G G} ^L _S ^L TA ^Y Y SE ^{Q N} LLNL _Q ^L EDYTE LLD VPNWD ^E T _Q ^{S S} _G ^{S S} _{S G} HNE L ^E T _{Q G} HNE ^E I _{G G} ^{L L E A} _S T _Q ^S _G ^S HNE GYAE EVDATT _G ^N YDI ^P M SEKVL KD ^N L GY _S ^{E A} _{S G} PLYVHK _G ^N Y _S ^{E A} _{S G} PLYVHK ^N L S _G Y _{S G} PLYVHK YVEI _S ^M RLLDDV LVEKHRVDY _S ^Y E YIAALI LYV _Q YIAALI YV _Q ^S YIAALI YV _Q ^S VL ^L KHLE EDKDL ANI _G ^E ILYIYK _G ^I VDPN ILYIYK ^I L GVDPN ILYIYK ^I L GVDPN KR _S KKMD ^K HWY VL GAEK KRYLPEE _S ^D DKRL PRT IKLNIP PRT IKLNIP PRT TIKLNIP MLELPKVRHK TFLFD ^K HT IKNVLL MLI ^D T QDIKNVLL MLI _Q ^D DIKNVLL KDDFLRINHK ^L ML S KDD ^Y MLI ^D T QD DVLV _G AK _{S S} ^K KDKIFDIDEKL KDKIFDIDEKL KDKIFDIDEKL RAYYVDK _G KTIRHRHL K AINEA R K AINEA R RKEEKEL ^K Y D KA SD _S ^R P AK _S ^K LP ^L R SV ^N K S _Q ^C K ^A AINEA QEKTLP _S ^L V _S ^N _Q ^C K _Q ^A EKTLP _S ^L V _S ^N _Q ^C VEE ^S ELKNHPYD K _Q ^A EKT S ^S NIK P _G E VKYILI VEEKMK DK EEKMK DK KD VEEKMK K KD LE ^A F G _S ^E I _{Q S} ILE V _S ^K _Q ^F NP _Q ^T LR ^{L S} EVRE _G ^S DY ^P KD V K _G AV Y _G ^P AV RE ^S D GDY _G ^P AV DA _S DPTFVEK ILI ^{S D} DL Q _S NKTT _{Q S} AAK KHV _Q ^{L S} EVRE _G ^S D S AAK KHV _Q ^{L S} EV S EAAK LD ILL LR ^N KTL C YDKKYILRI ^D TE YD ^L E G _Q ^Y INLM _G ^L PYKYD _G ^{L Y} E QINLM _G ^L PYKYD _G ^L _Q ^Y INLM ^L KHV GPYK DA _Q ^F KYI _G ^I VI _S ^D H DAALLD _S FY DAFYFDEFFKLRDAFYFDEFFKLRDAFYFDEFFKLR ELLELKKRK K DLDLDE ^I TE GLR ^E N ^{S I} LVFAPN LR QEKIDVKNY _G ^D A TH ^R _Q ^L ELVFAP G TKKKTHV _{Q S} ^I LRE STT TKKKTHV _Q ^S _S ^{I I} LRELVFAPN G _S TT TKKKTHV _Q ^{S I} _{S S} ^I TT LKALFIID ^I NIKVV GLTKRKKPT MKKLADTPRELE MKKLADTPRELE MKKLADTPRELE VRDNNEA ^I KH ^D VR _S ^E KTKINYPII VRF ALETTEP ^L _G PY _G VR SYLLLAL _Q ^L LMEADLLV ALD _S ^{Q S} L QE ^E IF RF L IF SI ^K LY V SH LD _S ^Q _Q ^S E _S ^E I ^K LY VRF Q _S R LD _S ^{Q S} L F QE ^E I SI ^K LY WHEIMF NN R HFYRNP L _Q ^S AVDALH _S FE ^L A G HAVDALH _S ^Q FE ^L A G HAVDALH ^Q _S H SFE _G ^L GYLYRM _G ^S DK ^I F STR _G ^W YNKTA ^L E EH ^W H GYK TDT _G YK RTDT _G YK LRT VIEKEPAVREVR ITYIK ^S _S F _S ^I GNEE ^K LR T ^W EI ^G P GLT I ^K L GDTEI ^G PT ^W DT L ^V _G LT STFYIELIF T _S ^V TKFFDPDK ^N I GL ^V I ST ^N _G DT GAVLED _S T _G ^N AVLED _S ^{L V} I ^{K N} _G DTEI ^G PT NATFFN F ^K L ^K AVLED N ^Q _S HENPFEKDLKR _S ^K T NPVHT HYA ^K V Q ^S _{S Q} NPVHT ^K V T _G ^L _G LT S V Q ^S _{S Q} NPVHT TYKKLA _{Q Q} Y YMA ^G GNKEEPV ^S _S FAY QT ^T FN ^D ELDIFF _Q A MT ^{G H G} P _Q F LN ^S Y GTLI ^E _{C Q} K ^E KV ^M HYA C V _Q ^M Y YMA ^G HYA _Q ^{K S} S _S LE I _G ^T TLI _Q ^E K _S ^{E H} K SLE I _G ^T TLI ^E _C ^{E H} KV ^M _{Q Q} Y QK _{S S} LE IKF PL _G L ^L _G DP GIDHK _S ^AF H SV ^N E IEK LL _G I IEK L LTV _G ^N I IEK L TV ^N I A _G I DHN ^Q DI S _S DEI TDHLVKKV ^A _{S G} ^G QV K _C ^L DHL _G ^Y NL ^S LTV ^N QRIK T DHL ^Y L GNL _Q ^S RIK T DHL ^Y L GNL ^S L QRIK LY ^G T LII _S ^AK V Q I AH GA _Q K _S ^K V HKI _Q ^{M L} YD ^G EDNPL _Q ^T SKLAI ^A E FAW ST ^L Y GA ^I K _Q ^K A YFAW L VAD _G ^L A ^D AH K _Q ^K A YFAW ^K T GA ^D AH Q ^I K _Q A QVAD IV _S DLE ^S _G K Q V _S ^L EDIII ^N E SEA IV ^Q P _Q ^D G _G ^Y RY ^K _{Q Q} ^L VAD ^L SVIEF IV ^Q _Q ^I G ^Y P GRY _Q ^KL _{Q S} VIEF IV _G ^{Q Y} P GRY _Q ^K _S ^L VIEF TE _G ^{N K} LK SDPEITV _G ^N N _S ^I ELILKDHKTL _S ^V VEFDI ILKNKI VEFDI NKI VEFDI YEVNVD DIK IYAA AEK ^T ILK ^T ILKNKI EEIDVI _S ^E YIK _Q ^K IPAI ^Y IRDDLKLT YD SDLVITKRY DE ^L P _S ^T G _Q ^K E N E _Q ^MA E YD SKDE ^L _S AEK G ^K P QE ^MA E YD _S AEK Q _S KDE _G ^{L K} P QE E _Q ^MA E SK ⁰ IMIEKN ^K ADDDDIVRRKLNEE _S ^F K _G ^D _S K _G ^D _{0 G} ^{K T} RVAT IL ^K HA NEE ^F N SK ^D E G HA LNEE ^F N TK ALA _S VIEA _G HD RKKKAN AN A T _S ^K YL ^I K S KKAN ^S A T ^K HA SYL _S ^I O M _G L _G ^Y L K K L K N K E M _G ^N _G ^{N Y} F G N Y I ^Y II Q K N K R M A K K ^S A Q N ^F T _S YL ^I KL S KK S Y K N L T M A K K _Q ^S N _S ^F Y K N L T M A K K _Q N _S ^F Y K N L T ₆ ^W

0 ^{5 0} _{1 7} ^{. .} _{7 5} ⁷ 1 _{2 3 4 5} ⁹ ₉ 0 ^{0 0 0} ₁ ⁸

1 _{8 2 2 2 2 B 7} ⁴

F _G L ADVF _G A KEEAATF F _G L TADVF ^P F _G L LTADVF

NR ^E LT Q V ^P F _G I T FD NR ^E L Q RV R _Q ^{E P} F _G L LTADVF ^P KY _G ^I A ^L R SIL _S ^{D V} _C ^G _Q NRE G LK L ^E VKL SVMNLV KY _G ^I A _S ^L IL _S ^D _C ^VG _Q N G KY _G ^I A ^L RV SIL _S ^{D VG} _Q NR ^E C _G KY ^I _{Q G} A ^L RV SIL _S ^D _C ^VG _{Q G} KKEIH E NY ^H KY Q KKDE EFIKPVV KKEIH E Y _Q ^H KKEIH E NY _Q ^H KKEIH E IVLKK _Q ^R D _G ^K L E IVEL N TR IVLKK _Q ^R D ^K N GL VLKK _Q ^R D _G ^K L E IVLKK _Q ^R D ^K NY _Q ^H GL KIDEPRVRY _Q ^K V KIEF F ^Q RKY GKVVYE KIDEPRVRY ^K E I QV KIDEPRVRY _Q ^K V KIDEPRVRY ^K E QV KHELLDINAPY KH DINAPY KHELLDINAPY KHELLDINAPY KAEFVEKEDDA KA ^Y Y VKPVKAL KHELL SE MFAELVI KAEFVEKEDDA KAEFVEKEDDA KAEFVEKEDDA EL YKFLT FLT L YKFLT TA _S ^Y E ^{Q L} EL ^E F V S _{G G} ^L _S TA _{S G} ^A K _S ^T _G ^{Y K} L ST ^E EL YK I ^{Q L} E G _S ^L TA _S ^Y E I ^Q _G ^L EL KFLT G ^{L E} I _S TA ^Y Y SE ^{Q N} L _{Q G} ^S HNE AA E MPT ^P _Q TA _S ^Y E SF ^E T _Q ^{S S} _{G G} HNE L ^E T _Q ^S _G ^S HNE ^E I ^S _{G G} ^L _S ^L ST _Q ^S _G HNE GY _S ^{E A} _S T GPLYVHK ^N L YI Y _Q ^L IVADE ^N L GY _S ^{E A} _{S G} PLYVHK _G ^N Y _S ^{E A} _{S G} PLYVHK ^N L ^{E A S} _G Y _{S G} PLYVHK YIAALI LYV ^S _G Y Q YIT LTADVF I LYV _Q ^S YIAALI YV _Q YIAALI YV _Q ^S ILYIYK _G ^I VDPN ILI _Q ^D V ^P YIAAL D ^V K _G ^I VDPN ILYIYK ^I L GVDPN ILYIYK ^I L GVDPN PRT LNIP PRKI ^L R SIL _{S C} ^G _Q ILYIY G PRT IKLNIP PRT IKLNIP PRT TIKLNIP MLI ^D TIK QDIKNVLL MLII H E Y _Q ^H MLI ^D T QDIKNVLL MLI ^D T QDIKNVLL MLI _Q ^D DIKNVLL KDKIFDIDEKL KDKK K _Q ^R D ^K N GL DIDEKL KDKIFDIDEKL KDKIFDIDEKL K INEA AK PRVRY ^K E KDKIF QV K AINEA R K AINEA R K ^A A QEKTLP ^L R SV _S ^{N C} K Q K _Q ^A EV LDINAPY K _Q ^A EKTLP ^L R SV ^N K S _Q ^C K ^A AINEA QEKTLP _S ^L V _S ^N _Q ^C K _Q ^A EKTLP _S ^L V _S ^N _Q ^C VEEKMK DK ^P KDVEE VEKEDDA VEEKMK DK EEKMK DK KDVEEKMK K KD L VRE _G ^S DY _G AV E _Q ^Y KFLT E _G ^S DY ^P KDV GAV Y _G ^P AV RE ^S D GDY _G ^P AV Q ^S E S K KHV _Q ^L _S ^{S Q L} EVR AAK KHV _Q ^{L S} EVRE _G ^S D L ^Y EAA _S AAK KHV _Q ^{L S} EV S EAAK YD _{G Q} INLM _G ^L PYKYD ^L Y _{G S} ^L _Q ^L _S ^S GF ^E I ST ^S _{G Q G} ^S HNE YD ^L E G _Q ^Y INLM _G ^L PYKYD _G ^{L Y} E QINLM _G ^L PYKYD _G ^L _Q ^Y INLM ^L KHV GPYK DAFYFDEFFKLRDAFK PLYVHK DEFFKLRDAFYFDEFFKLRDAFYFDEFFKLR ELVFAPN VL LI LYV ^S DAFYF Q ELVFAPN LVFAPN TKKKTHV ^S LREL Q _S ^I _S ^I TTTKK ^I V _Q ^S _S ^{I I} LRE STTTKKKTHV _Q ^S _S ^{I I} LRELVFAPN STTTKKKTHV _Q ^{S I} LR S _S ^I TT MKKLADTPRELEMKK ^Q YK _G VDPN TKKKTH S TIKLNIP MKKLADTPRELEMKKLADTPRELEMKKLADTPRELE VRF IF YVRFV DIKNVLL VRF ALD ^Q L S _Q ^S E _S ^E I ^K L SH ^E IF RF L IF K FDIDEKL ALD _S ^{Q S} L QE _S I ^K LYV SH LD _S ^Q _Q ^S E _S ^E I ^K LYVRF SH LD _S ^{Q S} L F QE ^E I SI ^K LY Q ^W HAVDALH _S FE ^L ALD G HA _G NEA R LH _S ^Q FE ^L A G HAVDALH _S ^Q FE ^L A G HAVDALH ^Q _S H SFE _G ^L GYK ^{W N C} AVDA KLRTDT T _G YKA TLP _S ^L V _{S Q} ^W H GYK TDT _G YK RTDT VI _G DTEI ^G P GLT H MK ^P KD ^K LR T ^W EI ^G P GLT I ^K L GDTEI ^G PT _G ^W YK LRTDT N _G LT _G DTEI ^G PT ST _G AVLED _S ^{L V} I T _G ^N A RE ^S DK GDY _G AV ^V I ST ^N _G DT GAVLED _S ^{L V} T _G ^N AVLED _S ^{L V} I ^K NPVHT YA ^K V Q ^S _{S Q} NPVI _Q EAAK HVNPVHT HYA ^K V Q ^S _{S Q} NPVHT ^K V T _G ^N AVLED ^L _G LT S V Q ^S _{S Q} NPVHT _Q ^{S T} YMT ^G H C Y YMA ^G HYA C V _Q ^M Y YMA ^G HYA ^K GTLI _Q ^E K _S ^{E H} KV _Q ^M Y ^T YM SLE I _G TL ^Y LINLM ^L K GPYK MA ^G GNFDEFFKLR ^T Y GTLI ^E _{C Q} K ^E _S ^H KV _Q ^M SLE I _G ^T TLI _Q ^E K _S ^{E H} K SLE I _G ^T TLI ^E _C KV ^M _{Q Q} Y QK _S ^E _S ^H LE IEK LTV _G ^N IIEKAWAPN LRIEK LL ^N DHL ^Y LL GNL _Q ^S RIK TDHL ^S LTV _G IIEK L LTV _G ^N IIEK L TV ^N I S ^{I Y} _G I YPTHV _{Q S S} ^I TT DHL _G NL _Q RIK TDHL ^Y L GNL _Q ^S RIK TDHL ^Y L GNL ^S L QRIK LYFAW H _Q A YF _G RADTPRELE FAW AH GA ^D A ^I K ^K DI ^I K _Q ^K A YFAW ^D AH K _Q ^K A YFAW ^K T IV _G ^{Q Y} P _{Q G} RY _Q ^KL _Q VAD _G ^L A SVIEFIV _G ^{Q S} L ^E IF LY ^L Y GA ^K _Q VAD _G ^L A VAD _G ^L A ^D AH Q ^I K _Q A K ^L _Q VAD Q _S ^L VIEFIV ^Q _Q ^I G ^Y P GRY _Q ^KL _{Q S} VIEFIV _G ^{Q Y} P GRY _{Q S} VIEF VEFDI LKNKIVEF ^K P _Q E _S I ^K H IV ^{Q Y} P _Q ^D G _G RY QEDALH ^Q _{S S} FE _G ^L VEFDI ILKNKIVEFDI NKIVEFDI YD ^T I EK EELRTDT PT YD ^{T L} _S AEK ^T ILK ^T ILKNKI DE _G ^{L K} P _S A QE ^M EYD DE _{Q S} ^A KDE _G N DTEI ^G LT DE ^{L K} P G _Q E N E _Q ^MA EYD SKDE ^L _S AEK G ^K P QK ^M EYD _S AEK F ^D _S KDE _G ^L A L ^D E _Q ^{A K} P QE ⁰ KLNEE ^F N SK _G HA K _Q ^S VLED ^L _{G S} V K _{G G} HA LNEE ^F N ^D E _Q ^MA E SK SK _{G 0} KKAN ^S A T _S ^K YL ^I KLN SKKAFRT HYA _Q ^{K S} KLNEE _S A ^K H S ^I K NEE ^F N SK YL _S KKAN A T _S ^K YL ^I K SKKAN A T ^K HA SYL _S ^I O M A K K _Q N _S ^F Y K N L T M A K L K E _C ^G E H K V ^M _Q KKAN Q Y M A K K _Q ^S N ^F T S Y K N L T M A K K _Q ^N N _S ^F Y K N L T M A K K _Q ^S N _S ^F Y K N L T ₆ ^W

0 ^{5 0} _{1 7} ^{. .} _{7 5} ⁷ 6 _{7 8 9 0} ⁹ ₉

8 ⁰ ₂ ⁰ ₂ ^{0 1 1} _{1 8}

2 _{2 B 7} ⁴

W NY _Q ^L IVADE W ANY _Q ^L IVADE W _Q ^L IVADE W ADE W E _Q ^R YLN _Q ^K _S ^L F ^H A GL ADVF L TADVF ^H ANY _Q ^L IV GL LTADVF _G VYKVN NR ^E LT Q V ^P F _G ^H Q NR ^E LTADVF ^H ANY P F _G L RV ^P F R _Q ^{E P} L ^{H P} E SA KY _G ^I A ^L R SIL _S ^D _C ^V _G ^{G I} _Q V GA ^L R SIL _S ^D _C ^VG _Q NR ^E L I _{Q G} KY _G A _S ^L IL _S ^D _C ^VG _Q N H _G KY _G ^I A ^L RV SIL _S ^{D V} _Q NR ^D K G _G DMTPVADF C _G KYILYYLEVFE KKEIH E NY ^H KY Q KKEIH E NY _Q KKEIH _Q KKEIH E NY _Q ^H IVLKK _Q ^R D _G ^K L E IVLKK _Q ^R D _G ^K L ^R E Y ^H KKIFKK QD ^K N GL VLKK _Q ^R D _G ^K L E LVATEK _G ^S _S ^K _G ^VG A GR KIDEPRVRY _Q ^K V KIDEPRVRY ^K E IVLKK QV KIDEPRVRY ^K E I QV KIDEPRVRY _Q ^K V YIL Y MPNYH KHELLDINAPY KHELLDINAPY KHELLDINAPY KHELLDINAPY KHL _Q ^E I _Q ^L IVLLE KAEFVEKEDDA KAEFVEKEDDA KAEFVEKEDDA KAEFVEKEDDA TATE EL YKFLT FLT L YKFLT ^M EDDYKR TA _S ^Y E ^{Q L} EL ^Y YKFLT ^{Y E} I ^S _{G G} ^L _S TA _S E ^{Q L} EL EI ^S _{G G S} ^L TA ^Y YK SE I ^{Q L} E G _S ^L TA _S E I ^{Q L L} ELEI _S RVDA G _{G S} TALKHILKD ^P V SY NL _{Q G} ^S HNE T _Q ^{S S} _{G G} HNE L ^E T _Q ^S _G ^S HNE KME GY _S ^{E A} _S T GPLYVHK ^N L ^{S E} _S T _{Q G} HNE ^E S _G ^A PLYVHK ^N L ^E LYVHK _G ^N Y _S ^{E A} _{S G} PLYVHK ^N LEE GYELPKD _G ^KH WE GN YIAALI LYV ^S _G Y Q YIAALI ^S _G Y _S ^A _{S G} P Q YIAALI LYV _Q ^S YIAALI YV _Q ^S YVEFLRVRHT _S ^E ILYIYK _G ^I VDPN ILYIYK ^I LYV GVDPN ILYIYK _G ^I VDPN ILYIYK ^I L GVDPN VLYYVDINHKK PRT LNIP PRT TIKLNIP PRT IKLNIP PRT IKLNIP KREEKEKEY MLI ^D TIK QDIKNVLL MLI _Q ^D DIKNVLL MLI ^D T QDIKNVLL MLI ^D T QDIKNVLL MLE EFLKD _S ^R _S ^G KDKIFDIDEKL KDKIFDIDEKL KDKIFDIDEKL KDKIFDIDEKL KDK _G ^A TV NID K INEA ^{N C} K AINEA R EA R K PPPT _Q ^S _S ^S ILE K ^A A QEKTLP ^L R SV _{S Q} K _Q ^A EKTLP _S ^L V _S ^{N C} K AIN Q K _Q ^A EKTLP ^L R SV ^{N C} K S _Q K ^A AINEA QEKTLP _S ^L V _S ^N _Q ^C K _Q ^A LLLVEKD VEEKMK DK ^P KDVEEKMK KD VEEKMK DK EEKMK DK KD V ^I V QKYI R L VRE _G ^S DY _G AV EVRE ^S DK GDY _G ^P AV EVRE _G ^S DY ^P KD V GAV Y _G ^P AVL _S ^E IETK ^I L GVV _S ^D _Q ^V Q ^S E S K KHV _Q ^L _S ^S AAK KHV _Q ^{L S} EVRE _G ^S D L ^Y EAA ^L _S AAK YD _{G Q} INLM _G PYKYD ^L EAAK HV _Q ^L _S ^S G _Q ^Y INLM ^L K GPYKYD ^L E G _Q ^Y INLM _G ^L PYKYD _G ^{L Y} E QINLM ^L KHVDT DVKRK K GPYKYD ^I I GAFIKNH _G ^D AD DAFYFDEFFKLRDAFYFDEFFKLRDAFYFDEFFKLRDAFYFDEFFKLRNADKNEIDIKHV ELVFAPN VFAPN LRELVFAPN LVFAPN TKKKTHV ^S LREL Q _S ^I _S ^I TTTKKKTHV _Q ^S _S ^I _S ^I TT TKKKTHV _Q ^S _S ^{I I} LRE STT TKKKTHV _Q ^S _S ^{I I} LRELEKTEA APYL STT THEIMLP _S ^L MKKLADTPRELEMKKLADTPRELE MKKLADTPRELE MKKLADTPRELE LKLYRT ^F KLK QILR VRF ^S IF YVRF ALD ^Q L S _Q E _S ^E I ^K L SH ^Q LY VRF S ^S L QE ^E IF SI ^K H ALD _S ^{Q S} L QE ^E IF RF ^{Q S} L IF SI ^K LY V SH LD _{S Q} E _S ^E I ^K LY VRDKE ^S N GDKTTR SH LFYI _S ^E ATREVT WHAVDALH _S ^Q FE ^L ALD G HAVDALH ^Q _{S S} FE _G ^L AVDALH _S ^Q FE ^L A G HAVDALH _S ^Q FE ^L A G HTFFNLTF GYK ^K LRTDT T _G ^W YK ^K LRTDT PT ^W H GYK TDT YK RTDT VI _G DTEI ^G P GLT _G DTEI ^G LT ^K LR EI ^G PT _G ^W GLT I ^K L GDTEI ^G PT _G ^W YKEKE ^KL E GLT ST _G ^N AVLED _S ^{L V} I ^N TE ^N F Q ^Q _{S S} Y SFA AVLED ^L _{G S} V ^V I ^N _G DT ED _S ^{L V K} V ^S _S T _G T _G ^N AVLED _S ^{L V} IK NPVHT YA _{Q Q} NPVHT HYA _Q ^{K S} _S T _G AVL ^S HYA ^K V Q ^S _{S Q} NPVHT ^K V ^S _S TF _Q ^{A A} KV _Q T PRT _S DVP ^S P _G ^L Q _Q N L _G LT TYMT ^G H C ^T A _C ^{G M} _Q NPVHT QY GTLI _Q ^E K _S ^{E H} KV _Q ^M Y YM SLE ^N I _G TLI _Q ^E K ^E KV S _S ^H LE ^T YMA ^{G E} KV _Q ^M Y YMA ^G HYA C V _Q ^M Y F VK EV S _S ^H LE I _G ^T TLI _Q ^E K _S ^{E H} K SLE I _G ^T E _Q ^G VK _Q ^L HI ^{S T} VI S _Q IEK LTV _G IIEK ^N I _G TLI ^E _{C Q} K DHL ^Y LL GNL _Q ^S RIK TDHL ^Y LL _G I IEK LL ^N GNL ^S LTV QRIK ^S LTV _G I IEK L LTV _G ^N I IR IELHKI _Q ^L _Q ^S QRIK T DHL ^Y L GNL _Q ^S RIK T DY _G ^N _S ^K DRDDLE LYFAW H AW ^K T DHL _G ^Y NL AH GA ^D A ^I K _Q ^K A YF ^D AH ^I K _Q A FAW ^I K _Q ^K A YFAW ^D AH K _Q ^K A TEITP ^N N D _G I K ^L _Q VAD _G ^L A _Q IV _G ^{Q Y} P _{Q G} RY _{Q S} VIEFIV _G ^{Q Y} P _Q AD ^L Y GA GRY ^K _Q V Q _S ^L VIEF IV ^{Q Y} P G _G RY ^KL _Q VAD _G ^L A VAD _G ^{L Y} VNV SMEV Q _S VIEF IV ^Q _Q ^I G ^Y P GRY _Q ^KL _{Q S} VIEF IVLVE ^I TDVK GNYVK ^K I QT VEFDI LKNKIVEFDI ILKNKI VEFDI NKI TEK IM RVA YD P ^T I SAEK ^T ILKNKI VEFDI ^T AEK ^T ILK DE _G ^L _Q ^K E E ^M E Q ^A YD P _S AEK D _S KDE _G ^{L K} _Q E ^A E YD SKDE ^L _G ^K P _{S Q} E N E _Q ^MA E YD SKDE ^L _S AEK G ^K P QE ^M E YEL ^Y A GLKD _S ^S VIE _S ^A Q _S ^A KEE A ^N L ANNL ⁰ KLNEE ^F N SK _G HA EE ^F N SK ^D E _Q ^M G A KLNEE _S ^F K _G ^D _G F ^S L QNR ₀ KKAN ^K HA NEE ^F N SK ^D E G HA M _Q ^F Y SA T _S ^K YL ^I KLN SKKAN ^S A T ^K H SYL _S ^I KKAN KAN A T _S ^K YL ^I K S K DAHI _Q ^MA L F N _S ^F Y N N L T M A K K ^S A Q N ^F T _S YL ^I KL S K S ^G P _S O M A K K _Q N _S Y K N L T M A K K _Q Y N N L T M A K K _Q ^S N _S ^F Y K N L T M ^K A G L _S R H E L T P A _G ^E

6 ^W 0 ^{5 0} _{1 7} ^{. .} _{7 5} ⁷ 1 _{2 3 4 5} ⁹ ₉ 1 ^{1 1 1} ₁ ⁸

1 _{8 2 2 2 2 B 7} ⁴

W KFR KR _G ^I D _G ^G H W T _G ^I D _G ^G H W V ^I F ^H I GKR ^I VV H W GD ^G H F _G ^H EL ^K T QKVD _G ^V YE F ^H KR GEL _Q ^K KVD _G ^V YE F ^H IKFR GKR ^I V ^G H W KR ^K T _G D _G ^G H F _G ^H EL _Q KVD _G ^V YE NREL ^K T QKVD ^V _{G G} YE NRLFYIIKNKN NRLFYIIKNKN NREL ^K T _G D QKVD ^V _G H GYE NRLFYIIKNKN KYLFYIIKNKN KYLNLMEKLAV KYLNLMEKLAV KYLFYIIKNKN KYLNLMEKLAV KKLNLMEKLAV KKE DLYPY KKE EDLYPY KKLNLMEKLAV KKE TLE ^E EDLYPY TLE _Q ^{E L} E SRVRADD TLE _Q ^E _S ^L RVRADD TLE EDLYPY TLE _Q ^{E L} EDLYPY SRVRADD SLE _{Q S} ^L RVRADD LENDINDW ^S LLENDINDW LE _Q ^E _S ^L RVRADD NDINDW SHLENDINDW ^S L DIKEKEHN ^F _{S S} HDIKEKEHN _S ^F _S ^S HLENDINDW ^S LLE SHDIKEKEHN _S ^F KADIKEKEHN ^F _S H S KAEKPFLKANE KAEKPFLKANE KADIKEKEHN _S ^F KAEKPFLKANE EMEKPFLKANE EMETLV K EMETLV KK EMEKPFLKANE EMETLV HKK TAETLV ^S HKK TAYLVT ^{S S} HK Q _S HR T _Q ^{S S} H SHR TAETLV HKK TAYLVT _Q ^{S S S} _S HR NLYLVT _{Q S} HR TFKLLVYP ^H TAYLV S TFKLLVYP _S ^H LYLVT _Q ^S _S ^S HR KLLVYP _S ^H GYTFKLLVYP _S ^{H N} L GYEVNT T LELI _G ^N YTFKLLVYP _S ^{H N} LTF GYEVNT ELI AVEVNT LELI AV ^I LELI ^N L GYEVN K _G ^I VNLE AVEVNT LELI AV HK ^I L I _G VNLE VL EHK _G VNLE VL ^K EHK _G VNLE AV S IKKIKD VL EHK _G ^I VNLE VL ^K E S PIKKIKD KR _S ^K KIKD KR ^S PIKKIKD VL ^K EH S ^S P S ^Y KR IKNE R _S ^K IKKIKD KR ^S MIKNE MI ^S PIK GMIKNE ^F _G IIKNE QRYEIDR _{S Q} MI ^F _G I QRYEIDR ^{S Y} K S _Q MI ^S P GIIKNE MI ^F _{G Q} RYEIDR _S ^S _Q ^Y KD _Q ^F RYEIDR _S ^{S Y} MI Q KDL MEA VDK KDL MEA DK D _Q ^F RYEIDR _S ^S _Q ^Y KDL MEA VDK KAL K _G ^I DFP _S ^I KKA _G ^K K _G ^I DFP ^I V SKKA ^K K G AL EA VDK DFP _S ^I KKA _G ^K SKK ^I MEA GDFP ^I VDK ^{K K} A SKKA _{G S} KATT HM ^K A SKATT VEATT ^S NYKHMVEELN _S ^MS NYK GD YRVEELN ^M NYKHM _S ^K KK ^I M GDFP _S ^I KKA _G ^{K K} AK _G ^I SKATT YKHM S _G ^S D PYRVEATT KHMVEELN _S ^MS N GD L LN _S ^M _G D PYRL ^S EENATT ^I P GELI L EEIATT _G ^I ELI L ^M NY PYRL IATT ^I PYR GELI R ^S E SEEIATT _G ^I ELIR _S EKMLLTFVLRR _S ^S EKMLLTFVLRR ^S ELN _{S G} ^S D SEEIATT _G ^I ELI R ^S EE SEKMLLTFVLR YD KMLLTFVLRYD KREE RTTT YD E TTT YD KMLLTFVLRYD REE RTTT DA _G ^L KREE TTDA _G ^L VEPK _S ^F NEVE DA ^L KRE GVEPK ^F R SNEVE DA _G ^L KREE TTT DA ^L K GVEPK _S ^F NEVE DLFVEPK ^F RT SNEVEDLFFIDVRR LY DLFFIDVRR LFVEPK ^F R SNEVE DLFFIDVRR LY T FIDVRR YT KFEIPF _S ^K H T VKFEIPF ^K LY D SH L ^A V QNKFEIPF ^K L SH ^A V YRLEI E _G ^L L _Q ^A NYRLEI FE ^L T G L ^A VFIDVRR LY T FEIPF _S ^K H QNKFEIPF _S ^E H ^A VK QNYRLEI VRKYRLEI FE ^L L _Q N G RKFV EI ^Q F S PT KFV EI _S ^Q RKYRLEI FE ^L L G RKFV EI ^Q FE _G ^{L W} _S PT SLFFV I _S ^Q T _S ^V LFDA _Q LHV _G ^G LI ^V R SLFDA _Q ^W LHV ^G PT GLI _S ^V LFFV WHNDA ^W E QLHV ^G P GLI NDL HNDA ^W EI _S ^Q QLHV ^G PT _S ^V LFDA _Q ^W LHV _G ^G LI GLI GY ^E NDL L E KNDL ^W HN Q ^S K GMEI ^{K S W} HN ^{E S} K ^{S W G} EI ^K L Q _{Q G} Y KNDL ^W HN ^S KNDL S ^V I _Q ^G _{Q G} MEI ^K L Q ^S _G Y Q I _Q TEETD ^A _{Q S} I ^F _{Q G} Y SH ^G _{Q G} M QTEETD _S ^A I _S ^F H I _Q ^G _Q ^E _G ^S MEI ^K L Y _Q ^E _G MEI ^K L ^{S S} _G A _Q I _Q ^G TEETD ^A _{Q S} I ^F _{Q S} H ST ^N TEETD _S I _S ^F H ^V _{Q S} T AMRDYKENI ^V I ST DYKENI _S ^V T ^{A N} TEETD _S I _S ^F H _S ^V T AMRDYKENI NP _G AMRDYKENINP _G ^{N H} DKT LTAI NP ^N AMR G DKT LTAI NP _G AMRDYKENI NP _G ^N KT LTAI TYV _G VNI _S ^D TK I _S ^D TK T YV G M ^H DKT GVNI ^D LTAI YV STK T _G ^T EI ^K T V _G ^H VN Q ^T Y G MEI LIK _Q ^{K T H} DKT TAI YV ^H D GVNI _S ^D TK K T _G ^T I _Q ^T LEI LIK _Q ^{K T} M IE _S ^{E M} LIK QRIVA _Q ^S I _Q ^T LIE _S ^{E M} _Q RIVA ^S _{G Q} I ^T M _G VNI ^D L ST QLEI K _Q ^{K T} MEI QLIE ^E IK ^K T Q E ^M _S ^M L QRIVA _Q ^S DHKIE _{S Q} RIVA ^S I _Q L QDHK ^Y PMAHRIEWDHK PMAHRIEWDHKIE ^E LI S _Q ^M RIVA ^S I Q DHK MAHRIEW L ^Y I HRIEW _G LTKIVNKI KIVNKI I MAHRIEW ^Y P TKIVNKI G _S F ^Y PMA GLTKIVNKI _G ^{L Y} I SFANLKDKM ^L I _G ^Y LT SFANLKDKM E _G ^L _S ^Y F ^Y P GLTKIVNKI _G ^{L Y} I _G L SFANLKDKM IK ANLKDKM EIK ^N E _G ^Y ILRH _S ^N T IK M E IK FILRH ^N E ST T _S ^Q WFILRH _S ^N TT ^{Q Y} WFILRH _S T IK GPDEPIHA T ^Q WF S _G ^Y PDEPIHA ^Q ANLKDK S FILRH _S ^N T T ^{Q Y} W DEPIHA Y _Q ^E L _G ^Y PDEPIHA ^E _S NKHK K PHV ^L T S Y _Q ^E L ^Y W GPDEPIHA ^E _{S G} P QLNKHK PHV _S ^L EK ^L Y _Q L ^A PHV _S ^L Y _Q ^E LNKH YNKHK ^A PHV _S EK ^V IYK _G ENMT EK K _G ^A ENMT EK ^Y NKHK HV ^L Y S EK YK _G ^A ENMT ⁰ KI _G IYK _G ENMTKI _G ^Y _S KT TNIRY KI ^{Y V} IY G _S KT KI _G ^{Y V} I SKT TNIRY ₀ KT ^{V F} TNIRY KI _G NMT N _S KT ^F TNIRYKT NET _S ^F YTVKRKT _S YTVKRKT ^V IYK ^A P GE IRY KT NET _S ^F YTVKR O M A _S N E T _S Y T V K R M A _S ^N D E Y L M D K R K M A ^N NET S D E Y L M D K R K M A ^N _S KT TN S N E T _S ^F Y T V K R M A _S ^N D E Y L M D K R K ₆ ^W

0 ^{5 0} _{1 7} ^{. .} _{7 5} ⁷ 6 _{7 8 9 0} ⁹ ₉ 1 ^{1 1 2} ₁ ⁸

1 _{8 2 2 2 2 B 7} ⁴

W R T _G ^I D ^G H W KR _G ^I D ^G H W KR T _G ^I D _G ^G H I F ^H K GEL _Q ^K KVD ^V _{G G} YE F _G ^H EL ^K T QKVD ^V _{G G} YE F _G ^H EL _Q ^K KVD _G ^V YE L ^H FFLDARL GDTEFM ^N Y I FFLDARL Y GV _G ^L L _G ^H DTEFM I _G ^N V _G ^L NRLFYIIKNKN NRLFYIIKNKN NRLFYIIKNKN NR ^K I KPT NR N E _Q ^K AKPT KYLNLMEKLTV KYLNLMEKLAV KYLNLMEKLAV KY _G ^{D R} N QY ^L E _Q A SIVKPLI KY _G ^D _Q ^R Y _S ^L IVKPLI KKE LYPY KKE DLYPY KKE EDLYPY KKIKVDVVALV TLE ^E ED Q _S ^L RVRADD TLE _Q ^{E L} E SRVRADD TLE _Q ^E _S ^L RVRADD II RA ^S KKIKVDVVALV SLLENDINDW LENDINDW DINDW FM _G ^Q LF ^Y EV F ^S L _{Q S} ^{I I} I _Q II A V I _Q ^S SEH FM ^Q R GLF _Q ^{Y I} E S V _S ^I EH SHDIKEKEHN _{S S} HDIKEKEHN ^F LEN S ^S L SHDIKEKEHN _S ^F RHLFTAE ^I V SAE KAEKPFLKANE KAEKPFLKANE KAEKPFLKANE KALDELPPN ^N I RHLFTAE _S ^I AE EMETLV ETLV K EMETLV ^K _G L KALDELPPN ^N I GL S TAYLVT _Q ^{S S} HKK EM SHR YLVT ^S HK Q _S ^S HR _Q ^{S S} HKK DLNEY _S ^K T DLNEY AVL ^K SHR TAERL ^R AVL Q NYF _Q ATAERL _Q ^{R N} LTFKLLVYP ^H TA S LTFKLLVYP ^H TAYLVT S TFKLLVYP _S ^H LLE K _G ^{H H} NYF ^K T QA GYEVNT LELI _G ^N YEVNT ^G LN LLE AV EHK _G ^I VNLE AV ^I LELI ^N L GYEVNT ^{L N I} LELI _G ^N YDI _S IM ^D A SD _G EL _G YDI ^L K _G A LN SIM _S ^D D _G ^G EL GVNLE LIEKHMV VL _S ^K KIKD VL ^K EHK _G VNLE AV S KKIKD VLDDKEK ^K H GA ^T KI LIEKHMV H KI Q LDDKEK _G ^K A _Q ^T KR ^S PIK GIIKNE ^S PIKKIKD VL ^K EHK S ^S PI KNE RYLPRVRHV _S ^AE V S KRYLPRVRHV _S ^A _S ^E MI _Q ^F RYEIDR _S ^{S Y} KR Q MI ^F _G MIKNE QRYEIDR _S ^{S Y} KR Q MI ^F _G MI QRYEIDR ^S K S _Q ^Y MLTFLDLNHEAVMLTFLDLNHEAV KDL ^I MEA ^I VDK DL ^I MEA VDK KDL MEA VDK DDYVEEDYRLT KDDYVEEDYRLT KAK _G DFP _S KKA ^K K G ^K AK _G DFP _S ^I KKA _G ^K K _G ^I DFP _S ^I KKA ^K K G T KFDKDKLT ^K T DKFDKDKLT SKATT NYKHM _S KATT HM ^K A SKATT K ^K D S KRY _S K _S ^K EIV NKRY VEELN _S ^M _G ^S D PYRVEELN _S ^MS NYK YKHM _S ^K GD YRVEELN _S ^MS N GD PYRPE ^T EIV VRRPE ^T ETI _S ^S IVRR L EIATT _G ^I ELIL EIATT ^I P GELI L EEIATT _G ^I ELI V ^F _G ETI ^S N SI QEPLKTEI KV ^F _G PLKTEI R ^S E SEKMLLTFVLRR ^S E SEKMLLTFVLRR _S ^S EKMLLTFVLRK _S ^K LFLTILRN _G ^R RK ^K _Q E SLFLTILRN ^R K GR YD KREE KREE ^F RTTT YD E RTTT YDP H VV DA _G ^L VEPK ^F RTTTYD SNEVEDA _G ^L VEPK _S NEVE DA ^L KRE GVEPK _S ^F NEVE DAA ^K Y SLV _Q ^S RK ^V ND YDP H V ND QEI DAA ^K Y SLV ^S V QRK _Q ^V EI DLFFIDVRR YDLFFIDVRR LY DLFFIDVRR LY D KLDILNYPLD D T KFEIPF ^K L SH KFEIPF _S ^K H T VKFEIPF _S ^K H ^L DLYN DL ^L KLDILNYPLD L ^A V QNYRLEI FE ^L T GL ^A V QNYRLEI E _G ^L L _Q ^A NYRLEI E ^L T _{Q G} IKENNE _G ^{I L} E _Q DLYN L E SF ^K T G IKENNE ^I D G R _S ^L F _G ^{K V} RKFV I _S ^Q T RKFV ^W EI ^Q F S PT KFV EI ^Q F S PT VRLKTLK ^L R SFL F VRLKTLK _S ^L FL SLFDA ^W E QLHV ^G P GLI _S ^V LFDA _Q LHV _G ^G LI ^V R SLFAA _Q ^W LHV _G ^G LI ALDIMIKDEV _S ^L F ALDIMIKDEV ^L F SF WHN DL NDL L FYKAIDKKYK HFYKAIDKKYK GY ^E KN Q _G ^S MEI ^K L Q ^S HN Q _G ^W Y ^E ENDL L Q _G ^S MEI ^{K S W} HN ^{E S} K EI ^{K S F} H HKNEAKRKKF _G ^F YHKNEAKRKKF VI _Q ^G TEETD _S ^A I _S ^F H I _Q ^G TEETD ^A _{Q S} I ^F _{Q G} Y SH ^G _{Q G} M QTEETD ^A _{Q S} I ^F _{Q G} Y SH KYIN IPA ^V IKYIN IFIPA ST AMRDYKENI _S ^V T AMRDYKENI ^V I ST DYKENI ^V I STKFFK ^P IF SF I A _S TKFFK _S ^P F NP _G ^{N H} DKT ^D LTAINP _G ^{N H} DKT AI NP ^N AMR G DKT LTAI NPFTDA ^N A _C ^L P NPFTDA ^N I SA ^L A CP TYV _G VNI _S TK T _G VNI ^D LT STK I _S ^D TK G MEI LIK _Q ^{K T} YV EI LIK ^K T V _G ^H VN Q ^T Y G MEI ^K T D ^{G E} ED _S ^A _{S Q} VFL D _S ^G _Q ^A VFL I _Q ^T LIE _S ^E _Q ^M RIVA ^S _{G Q} I ^T M QLIE _S ^E _Q ^M RIVA _Q ^S I _Q ^T LIE _S ^{E M} LIK _{Q G} ^T _Q ^F DI _G ^A _G ^{T F} D Q ^E E QADLPLDI _G ^A QRIVA _Q ^S IK ^A _Q ADLPL QT KNL IK _Q ^A T M I KNL DHK ^Y PMAHRIEWDHK ^{N Y} PMAHRIEWDHK PMAHRIEWDH ^S M I F _Q ^E I _S ^N EEADH ^{S N} T _S F _Q ^E I _S EEA L ^Y I _G LTKIVNKI ^{L Y} I _G LTKIVNKI _G LTKIVNKI ^N T _{S G} ^K AEVHKKKT Y _G EVHKKKT G _S FANLKDKM E _{G S} FANLKDKM ^Y I ^Y KDKM ^L Y V _G KK NRF _G ^L EV ^K A GKK DLNRF IK WFILRH _S ^N TIK ^N E _G ^L _S FANL ILRH ^N E _G E Q ^Y _S T IDDD ^V DL QITWVT ^I KIDDD _Q ^V ITWVT T ^E _{S G} PDEPIHA ^{Q Y} WFILRH _S T IK GPDEPIHA ^Q WF S _G ^Y PDEPIHA ^I K SELIVKKDIANL _S ELIVKKDIANL Y _Q LNKHK ^L T NKHK K PHV _S ^L K IIVYIIHL EK IVYIIHL EK ^A PHV _S Y ^E _{S Q} L ^A PHV ^L T S Y _Q ^E LNKH Y IYK _G ENMTEK ^V IYK _G ENMT EK K _G ^A DNMT ^Y E GTL _G ^Y EID ^S K _G TL ^Y I GEID ⁰ KI _G ^V _S KT TNIRYKI _G ^Y _S KT TNIRY KI _G ^{Y V} IY SKT _S V _G ^{E Y} N ^Y GI KLFAEKD ^S K SV ^{E Y} N G _G I ₀ KT ^F TNIRY KLFAEKD NNET _S ^F YTVKRKT NET _S ^F YTVKRKT NET _S YTVKRKT K T LT TK O M A _S D E Y L M D K R K M A _S ^N D E Y L M D K R K M A _S ^N D E Y L M D K R K M A ^E FLT TT S _G ^Y N L K _Q ^L R D N ^F K S M A _S ^{E Y} F G N L K ^L T Q R D N _S ^F

6 ^W 0 ^{5 0} _{1 7} ^{. .} _{7 5} ⁷ 1 _{2 3 4 5} ⁹ ₉ 2 ^{2 2 2} ₁ ⁸

1 _{8 2 2 2 2 B 7} ⁴

L FLVEHALLRL YFLVEHALLRL TAKAPYD L APYD I LDARLVEI L ^H Y GDTEDVVVKTTL _G ^H DTEDVVVKTT L ^H YFL GDTELMKTILI L ^H YFLTAK GDTELMKTILI L _G ^{H F} F GTEFM II NR IV VENR ^D NR IEHALLRNR IEHALLRNR NLE _Q ^K AN ^N L GT KY _G ^{D R} NKV QYYIEA _S ^D LYKY ^D _G ^R NKVIV VE QYYIEA _S LY KY _G ^{D R} N QYDVVVKTT KY _G ^{D R} N QYDVVVKTT KY _G ^D _Q ^R YTIVKN KKIKVKH ^D KKIKVKH N H KKIKVKVIV KIKVKVIV VE KKIKVDVVAD ^K T QD II RAEE ^L N H SL _G P _G ^L II YIEA ^D VE K SLY II RAYIEA _S ^D LY II A VFLL YI _G ^K LFLPPY PTYI ^K RAEE _S ^L L _G ^D P _G ^L II H _G LFLPPY PT YI ^K RA GLFKH I _G ^K LFKH N H ^L FM ^Q R GLF _Q ^{Y I} E S VLEF RHLFKRDVA _Q LVRHLFKRDVA _Q ^H LVRHLFKEE ^L N SL ^D H GP ^L Y G RHLFKEE _S ^L L _G ^D P _G HHLFTAE _S ^I A I KALDEK DDLI LDEK I KALDELPPY ALDELPPY ELEEYR _G ^{Y S} KA EEYR ^Y DDL G H M _Q ^S ELEEYRDVA ^H PT K QLVELEEYRDVA ^H PT KALDELPPN _G ^{G Q} QLVDLNEY NVLN ^S _{S S} N TAERLIM ^D H _Q EL SA ^I M SEHTAERLIM _S ^D A _S ^I EH TAERLK DDLI AERLK DDLI TAERL _Q ^{R N} LLD MV LD V HE R _G ^{Y S} T LLD R _G ^{Y H} NY AP GYDI _S ^L EE ^K HE I GH ^N L ^N L GYDI ^L M SEE _G ^K H ^N I LD GL ^N L GYDI _S ^L IM ^D H SA ^I M _{Q S} EH _G ^N YDI _S ^L IM ^D H SA ^I M _Q ^S SEH ^N LLE GYDI ^L K _G A _G ^Q LK SIM _S ^D DVLY FIEKHRIRY ^K _{G S} TFIEKHRIRY _S ^K MV E IEKHMV E VLEDKDLNNF _Q ^K AVLEDKDLNNF ^K T FIEKH QAVLEDKEE ^K H GH ^N I F LEDKEE ^K H GH ^N I LIEKHMV H RR KRYIPEEKN YIPEEKN LE KRYIPRIRY ^K _G L V LDNKEK _G ^K A _Q ^T RV S T KRYIPRIRY ^K _G L V S T KRYLPRVRHE MITFLFD ^G LEKR TFLFD I _G ^G EL MITFLDLNNF _Q ^K AMITFLDLNNF _Q ^K AMLTFLDLNHE _G ^Q _S ^S KDEYVLV ^A I _G ELMI SE IKDEYVLV _S ^A E KI KDEYVEEKN DEYVEEKN KA N KR ^T K Q ^A E A D ^G LE K GEL A ^G LE KDDYVEEDYTD GEL ^Q S ^{K K} TI TVM _S A _S ^{K K} N IKR _Q ^T S ^K T ^A E V ^A I SE ^K D ^K FD ^K T KFDKDKN _S P ^K _{S Q} ^S _Q LK GDTLLKEA ^{K S} _Q LKTVM _S A ^K A S ^K D S ^K F IKR ^T KI _S ^K Q E P ^K _S LV ^A I SE Q ^S _Q ^T KI _S K ^K D S EIV NKFI Q E PE ^A ETI _S ^S IVEE V ^F EPL VYVL ^I P _{Q S} V ^F _G DTLLKEA P _Q ^{K S} _Q L EPL L _S ^I V ^F _G DT QEPLKTVM _S ^A AV ^F _G DTIKR M _S ^A AV ^F _G PLKTEIF K ^S _{Q S} IILV _Q ^S K KLTK ^S _{Q S} IILV ^S VYV QK LT K _S ^S IILTLLKEA ^S _Q EPLKTV I K _S IILTLLKEA ^K _Q E SLLLTILRN ^V YDKK VLN _Q ^L KRYYDKK LN ^L K QKRY YDKK _S YDKK L VYVL ^I K Y _S YDP YH V ^L _{G S} L DAAE _Q N DYVRRDAAE ^Y V QN RRDAAE ^Y L QV ^S VYVL QK KLT DAAE _Q ^Y V _Q ^S K KLT DAA ^{K V I} _S LI ^S V QRK _Q YF D IDE _G IDE ^I DYV G DV LN _Q ^L KRY D T ^L D QEAYLK ^L DV KD SKN _G ^R RT ^L D QEAYLK _S ^L KN ^R KD ^L DIDI GRT _Q EAYD ^L DIDILN _Q ^L KRY DLKLDILNYPKK VKAKNIKDR DVKAKNIKDR ND VKAKNE ^I DYVRRT _Q EAYD DYVRRTHELYN G DV KAKNE _G ^I V KIKENNE ^I D G ^L PF G _S ^L L VRLKTDIDF ^V N QEI RLKTDIDF _Q ^V EI LKTLK _S ^L KN ^R KV GR RLKTLK ^L D SKN _G ^R RVRLKTLK _S ^L FLK _G ^A SLEIMEAK PLV _S ^V LEIMEAK LV ^V R SLEIMIKDR ND _S ^V LEIMIKDR WHFFRNPI _S ^Q FRNPI ^Q P S E FFR IDF _Q ^V EI HFFR ^V ND ALDIMIKDEVIP QEI HFYK GYNRTE FV ^Y E SF ^S HF G _G ^W YNRTE FV _S ^Y F _G ^{S W} H GYNRT _Q ^E AK LV _G ^W YNRT ^E IDF QAK PLV _G ^W YHKN ^E IDKKI GAKRKL _G ^{A V} ITYIP _G ^{S L} YIP _G ^S PI ^Q P S E ITYINPI _S ^Q STKFFNA ^A LL L IT Q V _S F _S ^V TKFFNA ^A LL Q ^L L TYIN SF ^V I STKFFE _S F _G ^S _S ^V TKFFE F ^Y E IKYINPIFI NPFNNDLP _S ^N KYKNPFNNDLP ^N V SKYKNPFNNE ^S FV ^Y V _S F _G ^S _S ^V TKFFK ^N G LL PFNNE _G ^S L L NPFADP ^S F G ^N T _{S S} ^F SANT T ^F N ^E EL IKRKF A _Q ^{A L} L N SF V _S ^L F FD NP _Q ^A VFIL G _{Q Q} ^A L _Q ^N ILVPA _G ^{T F} N Q ^E EL IKRKF N Q L _Q ^N ILVPA _G ^T _Q ^{F E} EA LP ^N V SKYK _G ^{T F} N Q ^E EAA ^A L Q IK _Q ^P T _S DVHTTLAIK _Q ^P T _S ^A DVHTTLAIK ^P _{Q Q} T ^A D SI ^P _Q DLP _S ^N KYK _G ^T K ^E E QADIPLDNK DH ^N IKRKF IK _Q T _S ^A I IKRKF IK _Q ^A T M I LTT DIRKPDH TT ^K EDIRKP DH _Q ILVPADH TF _Q ^N ILVPADH T _S ^S F _Q ^E I ^N KKL SEY IY _G ^K E ^K E SAIIFI VHTTLA ^L T G AVHTTLA Y _G ^N EVHKK ^L GEL _G KVRDN ^A Y _G ^L G _G ^I EL ^K E _S AIIFI ^L TTF G ^K EA GKVRDN I _G ^{A I} Y GKL _G KKEDIKKP ^I Y GKL ^K E GKKEDIRKP _G ^L EV ^K A GKK DLN ^G _{S C} I IKAEDIYYV ^D I SNIIKAEDIYYV _S ^D NI IKAEDDAIIFI IKAEDDAIIFI AELIVKD AELIVKD RDN I _G ^A AELIVRRDN ^A KIDDD _Q ^V ITWE SELIVK Y A MKE ^Q KKKA SPKETY ^Q KKKAAELIVR YYV _S ^D NI Y A MLYYV ^D I _G ^I KDIAE _S ^{F Y} _S NI YEK IVYIIL K _Q ^E L _G ELA ^Y MKE _S PKET Y A ML LDDLFK ^E T QL _G ELA F K _Q ^E L _G ^Y EID KKKAK _Q ^E L _G ^Y EID KKAPEL ^F V GEID ^{E 0} KLFADDE _Q RWITKLFADDE ^L DDL QRWIT KLFADKE _S ^Q PKET KLFADKE ^Q K SPKET KLFAEKD ^N K SV ^E Y _{S G} T ₀ K ^{T N Y} FH DIVNLK ^Y FH DIVNL K A DDLF K DLF KT LT TV _Q ^L O M _{G G G} N Y _S ^G I R I K L M _G ^T _G ^N _G N Y _S ^G I R I K L M _G ^{T N Y} FL G _G N L E _Q ^L R W I T M _G ^{T N} FLA G _G ^Y N L E ^L D Q R W I T M A _S ^{E Y} F G N L K ^L T Q R D P Y ₆ ^W

0 ^{5 0} _{1 7} ^{. .} _{7 5} ⁷ 6 _{7 8 9 0} ⁹ ₉ 2 ^{2 2 3} ₁ ⁸

1 _{8 2 2 2 2 B 7} ⁴

I KHRIKAW YFLLEP LE _S ^{Y Y} L ^H A GAERDIRDD ^K L S L _G ^H NTE VK ^V K L YFLLE _{S G} ^P K L SD L ^H YFL GNTE _{G S} ^P D L _G ^H N ^V K L YFLLE _S ^Y NRYLPEE ^{D N} HKK NR ^D VK ^V TE VK _{G S} ^P D L _G ^H NTE VK _G ^VP K SD SVMLDV NR N _S VMLDV NR N _S ^D VMLDV KYEFLFD _G AKV KF ^D N _S ^D VMLDV NR G _Q ^R YYIKLFY KF _G ^{D R} N QYYIKLFY KF _G ^D _Q ^R YYIKLFY KF _G ^D _Q ^R YYIKLFY KKEYVVV NNRA K KVNNRA IIDEKTI ^K HRLNEK SHPV II ^I KVNNRA QRTKEV ^G D EK KV GL II _Q ^I RTEEV ^G D E GL II _Q ^I RTEEV ^G D EK VNNRA SII TYID _G ^E ALFL ^K YH IALFL V _G ^K YH IALFL ^K _G L II ^I K QRTEEV ^G D GYH FL ^K _G L GYH QH ^A ELN GDILTHLVL ^H I SHLFKR ^P V _{G Q} DIKK _S ^H HLFKR _Q ^P DIKK _S ^H HLFKR ^P V QDIKK ^H IAL SHLFKR ^P V QDIKK KA _S ^K EPY LNKK KALDEK P KALDEK KP KALDEK VKP KALDEK VKP DLLVLI _Q ^S VLNK _S ^K DLVEYR ^H VK G _S ^K ATE DLVEYR _G ^{H K} V SATE DLVEYR _G ^H _S ^K ATE DLVEYR _G ^H _S ^K ATE TALDYILKENALTAERLIMPNDD TAERLIMPNDD TAERLIMPNDD TAERLIMPNDD NLLILE NR LE IVLWV LLE MIVLWV LLE MIVLWV GYELDE _G ^I DL _G ^{Y Y} D SI ^N L GYEI ^L M SEKDYYKD _G ^N YEI _S ^L EKDYYKD _G ^N YEI _S ^L EKDYYKD ^N LLE GYEI ^L MIVLWV SEKDYYKD LIL EKHRV AFH EKHRV FH VEKHRV AFH LVEKHRV AFH VLD ^L HLK GLLK ^F KVLRLV SYALTVLEDKDL _S ^D DKI ^G LV G VLEDKDL ^D A SDKI ^G L G VLEDKDL _S ^D DKI _G ^G VLEDKDL _S ^D DKI _G ^G KRE DLMREKRYLPEE HKNL KRYLPEE KNL KRYLPEE HKNL KRYLPEE HKNL MIE ^K TDI SMKANDNIYMLTFLFD _G ^K ATK MLTFLFD ^K H GATKKMLTFLFD _G ^K ATKKMLTFLFD _G ^K ATKK KD ^Y FRNPKF L D ^Y VLVRHKA _S ^K KDD LVRHKAN KDD LVRHKAN KDD VLVRHKAN KM _S KEE IN _Q ^S H ^L KD GKV TINHRHL KV ^Y V G TINHRHL KV ^Y SKDYIE _G ^{S K} _G INHRHL KV ^Y V S ^K T LKEYPYD AK _S ^{K K} LKEYPYD AK ^K _{G S} ^K TINHRHL QLKEYPYD PD FFNP ^Y AKETAK SRFPVPE ^S _Q LKEYPYD AK ^K _{G S} ^K TLKDILI PE ^S _{Q G} NTLKDILI PE ^S NTLKDILI VP _S ^K D ^R DLRFLL ^F _G NTLKDILI PE ^S _{Q Q} EPL LRVP ^F _G N QEPL LLRVP _Q ^F EPL LLRVP ^F _{G Q} EPL NLLR KT D _S L P ^S VP R ^A L _Q KNLILV ^{S S} NL Q _S IK V _Q ^{S S} N SIK NLILV _Q ^{S S} N SIK YD _Q ^F E F _S ^S V _{S G} HYDPKYILTE ^T T KNLIL GE YDPKYILTE ^T T K ^{S S T} T KNLILV _{Q S} IK DALT _S ^A EVIA ^V IDAANLD R _S ^D LY DAANLD ^D _G E YDPKYILTE ^D _G E YDPKYILTE ^T T GE ELTVTKLHF ^S _{Q Q} LDLKLDE ^I L GVV H DLKLDE ^I LR _S LY DAANLD LR _S LY DAANLD R _S ^D LY GVV LKLDE _G ^I VV MTIRE D E _G ^N E YLKRK _G ^N N _G ^L T E YLKRK ^N H GN ^L D G T ^N H LKLDE ^I L GVV H L _G N ^L D G T YLKRK _G ^N N _G ^L VKK ^D V _S ^V E ^T T SV _Q ^Y E _G NIKNYKPT V _Q ^Y E _G ^L NIKNYKPT V ^Y E LKRK QE ^L Y GNIKNYKPT V ^Y E QE _G ^L NIKNYKPT VRE ^K M _{G Q} ^A SDINDKR _Q ^K KVRLKTKIDLPLI VRLKTKIDLPLI VRLKTKIDLPLI VRLKTKIDLPLI ALETVITYLKL LMEA ^I ELV ALELMEA LV LELMEA LV ^{I W} HLP KDFTK ^L ALE C HFYRNP _S F I _Q ^S FYRNP ^I E SF ^S A ^S ALELMEA ELV SF I _Q ^S GYDV _Q ^V LIAIV _G ^E E _G ^W YHKN E _S ^I EH ^W H GYHKN ^I I _Q HFYRNP ^I E SF HFYRNP SNE _S EH _G ^W YHKN ^I I _{Q S} EH _G ^W YHKN E _S ^I EH VIF YI _S ^KS N GDKE _G DKE IKYI ^KS NE S _G DKE STV ^L ELN GF ^L II ^S T SKN _S ^V IK FFNAKR ^N I KYI _S ^K GL ^V I STKFFNAKR ^N I TKFFNAKR ^N I IKYI _S ^KS N GDKE STKFFN NPKRN ^D E QIDTVA ^T _S TK SNPFAADIIF _S ^{K K} T NPFAADIIF ^K _G L _S ^V S T NPFAADIIF ^K _G L ^V AKR ^N I GL S T NPFAADIIF _S ^{K T} YKKWY PTPLP FD ^{K N} A _Q A FD L ^K T GNFAPT _Q ^{T E} EL _Q A D QAF ^D F S ^N F S LN ^T F GN ^E EL ^D F F _Q ^K S _S N ^T FD L F F GN ^E E QAF _S ^{D N} IKDDRTA ^D R Y _G ^T N CL ^S L SRRIE _Q ^A N ^{A S} DV _Q V _G ^G EL IE ^A _Q AF QN V _Q ^A V ^G L GEL IE _Q ^A N DV ^A _{S Q} V ^G LN _G ^T N ^E E A _Q AF ^D F S ^N F _Q A S LN GEL IE _Q N DV _Q ^A V _G ^G EL DH ^A KI NKYRKDH T _S K ^S D VPL RI DH QI ^{T N} T _S K ^V PL RI DH LY _Q KA ^Y K SRL I R Y _G ^N _Q I ^{T N} T _S ^S K ^V PL G D _Q I ^T RI DH T _S ^S K L Q E Y _G ^N D ^V P QI ^T RI GN ^N YEAIP _G ^E V _G ^R P _G ^L KV ^K ED GKLNI ^N _{Q S} E ^A E _G ED ST ^L Y GKI _G ^K KLNI ^N _{Q S} E ^A E Y ST _G ^L KV ^K E GKLNI _S ^N E _S ^A T _G ^L KV ^K E GKLNI ^N _{Q S} E ^A E ST IK _G L KI VIDDILHKEA IDDILHKEA IDDILHKEA DDILHKEA SEL ^D NI S ^Q NK GEKEI _S ^I ELIVKNDLVL _S ^{T I} V SELIV NDLVL ^{T I} V S _S ELIV VL _S ^{T I} VI SELIV YEM _S ^G K ^F E QKTNVM DITKLT YEK ^K NDL CDITKLT YEK ^K NDLVL _S ^T CDITKLT PELV ^Y IRDITKLT YEK I _C ^{K R} EFYKIE ^Q YEK GPEL _G ELTDVKRY PEL _G ^Y ELTDVKRY PEL ^Y I GELTDVKRY PEL ^Y I GELTDVKRY ⁰ KLKY _Q EDLKNFFKLFADD YIVKRKLFADD KLFADD ^E YIVKRKLFADD YIVKR ₀ K ^E YIVKR TLAL DRE ^L FK ^Y FH _G ^E _G KI E FH _G I KK H _G ^E KI O M _G F A W _G ^V _G ^L I N I _S K M ^N E G A _G N Y I ^Q KI S V N ^R KK E FH G R M _G ^N A _G ^Y N Y I _S ^Q V N ^R KK G R M _G ^N A _G ^Y N Y I ^Q K S V N _G ^R R M ^N E G A ^Y F G N Y I _S ^Q V N ^R K G R ₆ ^W

0 ^{5 0} _{1 7} ^{. .} _{7 5} ⁷ 1 _{2 3 4 5} ⁹ ₉ 3 ^{3 3 3} ₁ ⁸

1 _{8 2 2 2 2 B 7} ⁴

L FLLE _S ^{Y VP} K L YFLLE _S ^Y K L DVVL L ^H Y GNTE VK _{G S} D L _G ^H NTE VK _G ^V _S ^P D L ^H YFL GDTEAVVL ^KN L S _S L ^H YFLLEP GNTE VK ^VP K L YFLLE _S ^Y G _S D L _G ^H NTE VK _G ^VP K SD NR ^D VMLDV NR Y DAPYD NR N _S ^D VMLDV NR N _S ^D VMLDV KF _G ^{D R} N _{S Q} YYIKLFY KF ^D N _S ^D VMLDV NR G _Q ^R YYIKLFY KF _G ^{D R} N QYK _Q ^I ID F _G ^D _Q ^R YYIKLFY KF _G ^D _Q ^R YYIKLFY EK KVNNRA D EK AE ^E K SVVN ^G K G KK KVNNRA II _Q ^I RTEEV ^G L II ^I KVNNRA D KKIKV QRTEEV ^G L II LPPVEDL II _Q ^I RTEEV ^G D KK VNNRA K _G L II ^I K QRTEEV ^G D HIALFL V ^K _{G G} YH ALFL ^K _G H ^K RT GLY SHLFKR _Q ^P DIKK ^H I SHLFKR ^P V _G Y QDIKK ^H M SHLFK ^R EVVLL ITLFL _G YH FL ^K _G L GYH Q DA ^K HLFKR ^P V QDIKK ^H IAL SHLFKR ^P V QNIKK KALDEK LDEK P KALDEK _G ^{K P} H _{S S} ^H SHL KALDEK VKP KALDEK VKP DLVEYR _G ^{H K} VKP KA SATE DLVEYR ^H VK G _S ^K ATE DLEEYIM ^D N SLKAD DLVEYR _G ^H _S ^K ATE DLVEYR _G ^H _S ^K ATE TAERLIMPNDD TAERLIMPNDD TAERLMV PHI TAERLIMPNDD TAERLIMPNDD NLLE MIVLWV LE IVLWV LE EK ^K Y GANYR LLE MIVLWV GYEI _S ^L EKDYYKD ^N L GYEI ^L M SEKDYYKD ^N L GYDI _S ^P RVRDDLT _G ^N YEI _S ^L EKDYYKD ^N LLE GYEI ^L MIVLWV SEKDYYKD LVEKHRV EKHRV AFH LVEKHDLNHDLE LVEKHRV AFH LVEKHRV AFH VLEDKDL ^D AFH LV SDKI _G ^G VLEDKDL _S ^D DKI _G ^G VLEDKEEAAFDY VLEDKDL _S ^D DKI _G ^G VLEDKDL _S ^D DKI _G ^G KRYLPEE YLPEE HKNL KRYLPFDKHL RYLPEE HKNL KRYLPEE HKNL MLTFLFD ^K HKNLKR GATKKMLTFLFD _G ^K ATKKMLTFLLV ^{Q L} K LTFLFD _G ^K ATK MLTFLFD _G ^K ATK KDD RHKANKDD I ^S H SY ^G _{S G} M GKT KDD LVRHKA _S ^K KDD VLVRHKA _S ^K KV ^Y VLV G NHRHLKV ^Y VLVRHKAN KDDYVT KTDN V ^Y V G TINHRHL KV ^Y AK _S ^{K K} TI EYPYDAK ^K _G INHRHL KA S ^K T LLN ^K I K PE ^S _Q LK GNTLKDILIPE ^S _Q LKEYPYD AK ^K DKL S ^Q _S K _S ^{K K} LKEYPYD AK ^K _{G S} ^K TINHRHL QLKEYPYD VP _Q ^F EPL ^F _G NTLKDILI PE ^S ET QEPL LRV ^F _G NL QAPV ^S VI _G V ^S A Q PE ^S _{Q G} NTLKDILI PE ^S NTLKDILI QREIVH VP _Q ^F EPL LLRVP ^F _{G Q} EPL NLLR KNLILV _Q ^{S S} NLLRVP SIK TKNLILV ^S NL Q _S ^S IK _S LILILNR YDPKYILTE ^T EYDPKYILTE ^T T K ^T GE YDK YN ^{T L} I KNLILV _Q ^{S S} N SIK ^T T KNLILV _Q ^S _S ^S IK QL YDPKYILTE DAVNLD LR ^D _{G S} LYDAANLD LY DAA _S ^K LE ^I DV _{Q G} KE T DAANLD LR ^D _G E YDPKYILTE ^T T GE SLY DAANLD R _S ^D LY DLKLDE _G ^I VV LDE ^I LR _S ^D GVV H DLDLDLK _S ^I YE _G ^N ADLKLDE _G ^I VV T RK ^N H GN ^L DLK GT KNLVKE T ^N H LKLDE ^I L GVV H GN ^L D G T YLKRK _G ^N N _G ^L V ^Y E QE ^L YLK GNIKNYKPTV ^Y E QE ^L YLKRK _G ^N N _G ^L TH GNIKNYKPT VK ^E TNI SNNEIDEKH ^Y E LKRK QE ^L Y GNIKNYKPT V ^Y E QE _G ^L NIKNYKPT VRLKTKIDLPLIVRLKTKIDLPLI VRLKTAAKFKV ^M V C VRLKTKIDLPLI VRLKTKIDLPLI ALELMEA ^I ELV LMEA ELV ALKLMNPIEVEP ALELMEA LV ^S ALELMEA ELV WHFYRNP _S F ^S ALE Q HFYRNP _S ^I F I _Q ^S FYHE GYHKN NE ^I I SEH _G ^W YHKN EH ^W H P _S ^I F I ^{S I} _{Q G} YNKEP ^S FKIKL ^W HFYRNP ^I E SF _Q HFYRN G ^A RN YHKN ^I I SEH _G ^W YHKN E _S ^I EH VIKYI ^K _S ^S _{S G} DKE I IKYI _S ^KS NE GDKE A _Q F ^S L _{G S} Y IKYI ^K NE S _G ^S DKE STKFFNAKR ^N L _S ^V TKFFNAKR ^N I TYIN GL ^V I STKFFDLP ^{V N} I IKYI _S ^KS N GDKE NPFAADIIF ^K _{G S} TNPFAADIIF _S ^{K S} _Q AD _S ^V TKFFNAKR ^{V K} _G L _S TKFFNAKR ^N I GL KT NPFE ^S I _S PWKNPFAADIIF _S T NPFAADIIF _S ^{K T} FD F _Q VV L FD L F F _Q ^K A ^T FD L ^K T GN ^E EL QAF _S ^{D N} F _Q ^K A FD ^E EL F _Q A N ^A M QAF _S ^{D N} F LN ^T F G ^D _Q F S N _G ^T N VHL _S ^Y R _G ^K _G ^T N ^E E A _Q AF _S ^{D N} _G N ^E E QAF ^D F S ^N F _Q A S LN IE _Q ^A N ^S DV _Q ^A V ^G L GELIE ^A _Q N DV ^A _{S Q} V _G ^G EL I _Q ^KP _Q AV QK KT IE _Q N DV ^A _{S Q} V ^G LN GEL IE _Q ^A N DV _Q ^A V _G ^G EL DH ^V D NT _S K PL IDH T _S ^S K ^V PL RI DH ^S K ^S K PL LY _G I ^T R Q E Y _G ^N _Q I ^{T L} _S D _Q I ^N L SV H T _{S G} EKHDKK ^{I Y} D G _Q Y _G ^N D _Q ^V I ^T RI DH ^N T _S ^S K L Q E Y _G D ^V P QI ^T RI GKV ^K ED _Q ^V GKLNI _S ^N E _S ^A T _G ^L KV ^K ED GKLNI ^N _Q E _G ^V SE _S ^A T ^L Y GA LYLK ^L KV ^K E GKLNI _S ^N E _S ^A T _G ^L KV ^K E GKLNI ^N _{Q S} E ^A E ST IVIDDILHKEA DDILHKEA ^L NKI SEDVD ^N _{G Q} IDDIL SELIV DLVL ^T VI S _S ^I ELIV ^D TV _G ^K HKEA ^I VIDDILHKEA YEK I ^K N CDITKLTYEK ^K NDLVL _S ^{T I} D SELIIK ^{T D} _S VTIN ^I V SELIVKNDLVL _{S S} ELIVKNDLVL _S ^{T Y} _S LITDL YEK RDITKLT YEK RDITKLT PEL _G ELTDVKRYPEL ^Y I _C DITKLT YEA GELTDVKRY PAI _G ^{Y V} L QLNRKIVKPEL ^Y I GELTDVKRY PEL ^Y I GELTDVKRY ⁰ KLFADD YIVKRKLFADD YIVKRKKLAD DNVHL KLFADD YIVKRKLFADD YIVKR ₀ K ^N E ^Y FH _G ^{E Q} KI KK ^Y FH _G ^E VIRKT _G ^I K E H _G ^E I KK H _G ^E KI O M _G A _G N Y I _S V N _G ^R R M ^N E G A _G N Y I ^Q KI S V N ^R KK G R M _G ^{N N} F _Q ^D G _G ^Y N Y Y D R T Y L M _G ^N A ^Y F G N Y I ^Q K S V N _G ^R R M ^N E G A ^Y F G N Y I _S ^Q V N ^R K G R ₆ ^W

0 ^{5 0} _{1 7} ^{. .} _{7 5} ⁷ 6 _{7 8 9 0} ⁹ ₉ 3 ^{3 3 4} ₁ ⁸

1 _{8 2 2 2 2 B 7} ⁴

L FLLE _S ^Y K L YFLLE _S ^{Y VP} K L LE _S ^Y L YFLLE _S ^Y LLE _S ^Y L ^H Y GNTE VK _G ^V _S ^P D L _G ^H NTE VK _{G S} D L ^H YFL GNTE VK _G ^VP K SD L _G ^H NTE _G ^VP K L YF SD L _G ^H NTE VK _G ^VP K SD NR ^D VMLDV NR _S VMLDV NR ^D _S VMLDV NR ^D VK SVMLDV NR N _S ^D VMLDV KF _G ^{D R} N _{S Q} YYIKLFY KF ^D N ^D G _Q ^R YYIKLFY KF _G ^{D R} N QYYIKLFY KF _G ^{D R} N QYYIKLFY KF _G ^D _Q ^R YYIKLFY KK KVNNRA D KK NNRA K KVNNRA II _Q ^I RTEEV ^G L II ^I KVNNRA D KK KV QRTEEV ^G L II _Q ^I RTEEV ^G D K GL II _Q ^I RTEEV ^G D KK VNNRA HIALFL V ^K _{G G} YH ALFL ^K _G H IALFL V _G ^K YH IALFL ^K _G L II ^I K QRTEEV ^G D P _G YH FL ^K _G L GYH SHLFKR _Q DIKK ^H I SHLFKR ^P V _G Y QNIKK _S ^H HLFKR _Q ^P NIKK _S ^H HLFKR ^P V QNIKK ^H IAL SHLFKR ^P V QNIKK KALDEK LDEK P KALDEK KP KALDEK ^{H K} VKP KALDEK VKP DLVEYR _G ^{H K} VKP KA SATE DLVEYR ^H VK G _S ^K ATE DLVEYR _G ^{H K} V SATE DLVEYR _{G S} ATE DLVEYR _G ^H _S ^K ATE TAERLIMPNDD TAERLIMPNDD TAERLIMPNDD TAERLIMPNDD TAERLIMPNDD NLLE MIVLWV LE IVLWV LE MIVLWV LLE MIVLWV GYEI _S ^L EKDYYKD ^N L GYEI ^L M SEKDYYKD ^N L GYEI _S ^L EKDYYKD _G ^N YEI _S ^L EKDYYKD ^N LLE GYEI ^L MIVLWV SEKDYYKD LVEKHRV EKHRV AFH LVEKHRV FH VEKHRV AFH LVEKHRV AFH VLEDKDL ^D AFH LV SDKI _G ^G VLEDKDL _S ^D DKI _G ^G VLEDKDL ^D A SDKI ^G L G VLEDKDL _S ^D DKI _G ^G VLEDKDL _S ^D DKI _G ^G KRYLPEE YLPEE HKNL KRYLPEE KNL KRYLPEE HKNL KRYLPEE HKNL MLTFLFD ^K HKNLKR GATK MLTFLFD _G ^K ATK MLTFLFD ^K H GATK LTFLFD _G ^K ATK MLTFLFD _G ^K ATK KDD RHKA _S ^K KDD LVRHKA ^K M S KDD LVRHKA _S ^K KDD VLVRHKA _S ^K KV ^Y VLV G NHRHLKV ^Y VLVRHKA _S ^K KDD K ^K TI TINHRHL KV ^Y V G TINHRHL KV ^Y AK _S EYPYDAK ^K _G INHRHL KV ^Y V S ^K T LKEYPYD AK _S ^{K K} LKEYPYD AK ^K _{G S} ^K TINHRHL QLKEYPYD PE ^S _Q LK GNTLKDILIPE ^S _Q LKEYPYD AK ^K _{G S} ^K LKDILI PE ^S _{Q G} NTLKDILI PE ^S NTLKDILI VP _Q ^F EPL ^F _G NTLKDILI PE ^S _{Q Q} EPL LRVP ^F _G NT QEPL KNLILV _Q ^{S S} NLLRVP SIK TKNLILV ^S NL Q _S ^S IK ^S LLRVP _Q ^F EPL LLRVP ^F _{G Q} EPL NLLR Q ^S N SIK NLILV _Q ^{S S} N SIK YDPKYILTE ^T EYDPKYILTE ^T T KNLILV GE YDPKYILTE ^T T K ^T T KNLILV _Q ^S _S ^S IK DAANLD LR ^D _{G S} LYDAANLD LY DAANLD ^D _G E YDPKYILTE ^D _G E YDPKYILTE ^T T GE I R _S ^D DLKLDE _G VV LDE ^I L GVV H DLKLDE ^I LR _S LY DAANLD LR _S LY DAANLD R _S ^D LY GVV LKLDE _G ^I VV T RK ^N H GN ^L DLK GT KRK ^N H GN ^L D G T ^N H LKLDE ^I L GVV H GN ^L D G T YLKRK _G ^N N _G ^L V ^Y E QE ^L YLK GNIKNYKPTV ^Y E QE ^L YLKRK _G ^N N _G ^L T E YL GNIKNYKPT V _Q ^Y E _G ^L NIKNYKPT V ^Y E LKRK QE ^L Y GNIKNYKPT V ^Y E QE _G ^L NIKNYKPT VRLKTKIDLPLIVRLKTKIDLPLI VRLKTKIDLPLI VRLKTKIDLPLI VRLKTKIDLPLI ALELMEA ^I ELV LMEA ELV ALELMEA ELV ALELMEA LV LMEA ELV WHFYRNP _S F ^S ALE Q ^W HFYRNP _S ^I F ^I I _Q ^S HFYRNP _S ^I F ^S _Q HFYRNP ^I E SF I ^S ALE Q HFYRNP _S ^I F I _Q ^S GYHKN ^KS NE ^I I SEH _G YHKN NE _S EH ^W _G YHKN ^I I SNE _S EH _G ^W YHKN ^I _S EH _G ^W YHKN E _S ^I EH VIKYI _{S G} DKE I IKYI _S ^KS _G DKE _G DKE IKYI ^K NE S _G ^S DKE STKFFNAKR ^N L _S ^V TKFFNAKR ^N I KYI _S ^K GL ^V I STKFFNAKR ^N I TKFFNAKR ^N I IKYI _S ^KS N GDKE NPFAADIIF ^K _{G S} TNPFAADIIF _S ^{K K} T NPFAADIIF ^K _G L _S ^V S ^K _G L _S ^V TKFFNAKR ^N I GL KT NPFAADIIF _S T NPFAADIIF _S ^{K T} FD F GN ^E EL QAF _S ^{D N} F _Q ^K A FD ^E EL _Q A D QAF ^D F S ^N F LN ^T F GN ^E EL ^D F _Q A FD L F F _Q ^K A FD L ^K T T ^A _S N _G N _S ^N F S LN _G ^T N ^E E IE _Q ^A N DV _Q V ^G L GELIE _Q ^A N DV ^A _{S Q} V _G ^G EL IE ^A _Q AF QN V _Q ^A V _G ^G EL IE ^A _Q AF _S ^{D N T} N ^E E QA QN DV ^A _{S Q} V ^G LN _G F ^D F S ^N F _Q A A _S LN S _G EL IE _Q ^A N DV _Q V _G ^G EL DH ^N T _S K PL IDH T _S ^S K PL RI DH ^S D L ED _Q ^V I ^{T N} T _S K ^V PL RI DH ^{V L} Y _G I ^T R Q E Y _G ^N _Q I ^{T N} T _S ^S K PL G D _Q I ^T RI DH ^N T _S ^S K L Q E Y _G D ^V P QI ^T RI GKV ^K ED _Q ^V GKLNI _S ^N E _S ^A T _G KV _G ^K KLNI ^N _{Q S} E ^A E _G ED ST ^L Y GKV _G ^K KLNI ^N _{Q S} E ^A E ^L Y ST _G KV ^K E GKLNI _S ^N E _S ^A T _G ^L KV ^K E GKLNI ^N _{Q S} E ^A E ST IVIDDILHKEA DDILHKEA IDDILHKEA IDDILHKEA VIDDILHKEA SELIV DLVL ^T VI S _S ^I ELIVKNDLVL _S ^{T I} V SELIVKNDLVL _S ^{T I} V SELIVKNDLVL _S ^T _S ^I ELIVKNDLVL _S ^T YEK I ^K N CDITKLTYEK DITKLT YEK RDITKLT YEK RDITKLT PEL _G ^Y ELTDVKRYPEL ^Y IRDITKLT YEK IR GELTDVKRY PEL _G ^Y ELTDVKRY PEL ^Y I GELTDVKRY PEL ^Y I GELTDVKRY ⁰ KLFADD ^E YIVKRKLFADD YIVKRKLFADD FADD ^E YIVKRKLFADD YIVKR ₀ K ^E YIVKRKL NE FH _G ^Q KI ^R KK ^{E Y} FH _{G G} KI E FH _G I KK H _G ^E KI O M _G A _G ^Y N Y I _S V N _G R M ^N E G A _G N Y I ^Q KI S V N ^R KK E FH G R M _G ^N A _G ^Y N Y I _S ^Q V N ^R KK G R M _G ^N A _G ^Y N Y I ^Q K S V N _G ^R R M ^N E G A ^Y F G N Y I _S ^Q V N ^R K G R ₆ ^W

0 ^{5 0} _{1 7} ^{. .} _{7 5} ⁷ 1 _{2 3 4 5} ⁹ ₉ 4 ^{4 4 4} ₁ ⁸

1 _{8 2 2 2 2 B 7} ⁴

L RLIM _S ^D DKI _G ^G L YFLDVVL ^N DVVL L L ^H Y GED MV DTEAVVL ^K L S _S L ^H YFL GDTEAVVL _S ^K _S ^N L ^H YFLLE _S ^Y GNTE VK ^VP K L YFLLE _S ^Y G _S D L _G ^H NTE VK _G ^VP K SD NR ^D I _S ^L EK ^K HKNLL _G ^H GATKKNR Y DAPYD NR N _S ^D VMLDV NR N _S ^D VMLDV KF _G KHRVRHKANKF ^D NY PYD NR G _Q ^R YK ^I DA Q KID F _G ^{D R} N QYK _Q ^I ID F _G ^D _Q ^R YYIKLFY KF _G ^D _Q ^R YYIKLFY KKIDKDLNHRHLKKIKVAE _S ^E VVN ^G K G KKIKVAE ^E K SVVN ^G K G KK VNNRA II LPEEKYPYDII ^K RTLPPVEDL II RTLPPVEDL II ^I K QRTEEV ^G D KK VNNRA LL M _G ^K LY ^K _G L II ^I K E _Q RTKEV ^G D HM _G WLFD _G LY EVV SHLVVLV ^D DILI SNLLR ^H M SHLFK _Q ^R H _S ^K _S ^H HLFK ^R EVVLL IALFL _G YH FL ^K _G L GYH Q DA ^K HLFKR ^P V QDIKK ^H MAL SHLFKR ^P V QDIKK KA DKTIRIKTTKALDEK ^K DA G N _S ^P HL KALDEK _G ^{K P} H _{S S} ^H SHL KALDEK VKP KALDEK VKP D ^L TE EEDLEEYIM _S ^D LKAD DLEEYIM ^D N D _S LKAD DLVEYR _G ^H _S ^K ATE DLVEYR _G ^H _S ^K ATE T ^L _{G S} E ^A ELK GE LR _S LYTAERLMV YPHI TAERLMV PHI TAERLIMPNDD TAERLIMPNDD NLLEP ^T L Q VV H LE K _G ^K ANYR LLE EK ^K Y GANYR LLE LWV GYDVLI _Q ^S RK _G ^N N _G ^{L N} L GYD ^P E SRVRDDLT _G ^N YD ^P RVRDDLT _G ^N YEI ^L MIV SEKDYYKD ^N LLE GYEI ^L MIVLWV SEKDYYKD LVEKYILNYKPTLVE _Q ^I HDLNHDLE LVE ^I _{S Q} HDLNHDLE LVEKHRV AFH LVEKHRV AFH VLENLD DLPLIVLEDKEEAAFDY VLEDKEEAAFDY VLEDKDL _S ^D DKI _G ^G VLEDKDL _S ^D DKI _G ^G KRYLDE _G ^I YLPFDKHL FDKHL RYLPEE HKNL KRYLPEE HKNL MLT ^I ELV SF ^S KR QMLTFLLV H ^Q KRYLP S _G ^L MLTFLLV ^{Q L} K LTFLFD _G ^K ATK MLTFLFD _G ^K ATK KDD ^I NIK GL NE ^I I SEHKDDYVTI _S ^S Y _G ^G KT KDDYVTI ^S H SY ^G _{S G} M GKT KDD LVRHKA _S ^K KDD VLVRHKA _S ^K KA KT ^I K QIDKE IKA LKTDN V ^Y V G TINHRHL KA ^Y AK _S ^K VMEAKR ^N LAK ^K DKLKTDN S ^K I KA TLLN ^K I K K _S ^{K K} LKEYPYD AK ^K _{G S} ^K TINHRHL QLKEYPYD PE YRNPIF ^K _{G S} ^K TPE ^S ETLLN _S AK ^K DK S _Q PE ^S E L VI ^Q _{S G} V ^S A Q PE ^S _Q L _G ^Q V ^S F AV ^F _G N QTPV ^S VI QREIVH V ^F _G N QTPV _Q ^S REIVH VP ^F _G NTLKDILI PE ^S NTLKDILI V ^F KTE ^S _Q EPL NLLRV ^F _{G Q} EPL NLLR K ^T _{Q S} LYIK _G ^N F _{Q S} LILILNR _S LILILNR NLILV _Q ^S _S ^S IK K _S ^T LILV _Q ^{S S A} _S NK ^T _S IK YNKFFNA _Q V ^G L GELYDK YN DV _Q ^{T L} I K ^T QL YDK YN DV ^{T L} I K Q _Q L YDPKYILTE ^T T DAAEKDIPL IDAA _S ^K LE ^I _G KE E _G ^I E T DAANLD LR ^D _G E YDKKYILTE ^T T GE SLY DAANLD R _S ^D LY DLDEEL I ^T R Q ^{I A} EDLDLDLK _S YE ^N T DAA _S ^K L GADLDLDLK ^I K SYE _G ^N ADLKLDE _G ^I VV TK E ^D I _S ^N E _S TTH IKNLVKE T ^N H DLDLDE ^I L GVV H E _G N _G ^L TH YLKRK _G ^D N _G ^L VE _S T _S ^AF _{S S} VHKEA ^E TNIKNLVKE TH SNNEIDEKH VK ^E TN SNNEIDEKH ^Y E LKRK QE ^L Y GNIKNYKPT VK _S ^E _G ^L NIKNYKPT VR ^L AKK DLVL ^T VK SVRLKTAAKFKV _C ^M VRLKTAAKFKV ^M V C VRLKTKIDLPLI VRLKTKIDLPLI AL _Q LEN _Q ^V ITKLTALKLMNPIEVEP ALKLMNPIEVEP ALELMEA LV ^S ALKLMEA ELV WHFKKLNDVKRY HFYHE KL GYN ^S FKIKL HFYRNP ^I E ^{S W} _S F ^W P _S ^I F I _Q GDI YIVKR _G YNKEP ^S FKI G RN ^W HFYHE G N YHKN ^I I _Q HFYRN SEH _G YNKN E _S ^I EH VIT _S LK _G ^{L V} YINA _Q ^A F ^S L _G YNKEP SY TYINA ^A R QF ^S L _G ^W IKYI ^KS NE S _G DKE STKRIRD ^D KI K IT S N _G ^R R _S TKFFDLP ^V AD ^V I STKFFDLP ^V _S Y ^N I ITYI _S ^KS N GDKE NKFKDLML _Q ^V DNPFE ^S _Q ^S _Q AD _S ^V TKFFNAKR ^{V K} _G L _S TKFFNAKR ^N I GL AM ^S I _S PWKNPFE ^S I _S PWKNPFAADIIF _S T NPFAADIIF _S ^{K T} FNRDD RR ^V N QEI FN _Q VV FD L F F _Q ^K A FN GE LFH _G ^E NIPLN _G ^{T D} _Q F _Q VV L N ^A M QAVVHL _S ^Y R _G ^{K T} F G ^D _Q F VHL ^Y L SR _G ^K _G ^T N ^E E QAF _S ^{D N E} EL ^K T IK _Q ^P KNYIIK KI _Q ^K _Q ^P K ^G LN _G ^T VF ^D F S ^N F _Q A S LN DH ^S K ^V D KT I _Q ^KP _Q AV QK ^S K ^V D LKT IE _Q ^A N DV ^A _{S Q} V _G EL I ^K _{Q Q Q} ^P N DV _Q ^A V _G ^G EL LKW DK ^Y K SFDDH _S K PL ^{S V} _S D _Q I ^N L SV _Q I _S ^N V H T ^S K L LY _G DP _G ^T _Q ^V LNL F Y _G ^L _G EKHDKK ^{I Y} DH G _Q ^L _S D HDKK _G ^{I Y} D ^V I DH T _{S Q} Y _G ^N D _Q I ^T R Q E Y _G ^L D ^V P QI ^T RI GK ^L TLAPNV _S ^L F _G ^L A NKILYLK ^L Y _{G G} ^V EK LYLK ^L KV ^K E GKLNI _S ^N E _S ^A T _G ^L A ^K E GKLNI ^N _{Q S} E ^A E ST IK _{S G} ^A I DEKYK D _S ^L EDVD ^{N K} _G A G _Q ^L NKI SEDVD ^N SELVK ^S K SAEDKKF _S ^I ELIIK ^D TV SVTIN ^I D SELIIK ^D TV _G ^K _{G Q} VIDDILHKEA ^{L I} D _S DDILHKEA SELIV VL _S ^T _S YEA ENITTIPAYEA ^D _S VTIN ^I ELIVKNDLVL _S ^T SLITDL YEK ^K NDL Y _C DITKLT YEA RDITKLT PKI _G DFEYE APAI ^Y L _S ^D LITDL YEA G _Q ^V LNRKIVKPAI _G ^{Y V} L QLNRKIVKPEL ^Y I GELTDVKRY PAI ^Y I GELTDVKRY ⁰ KLLAAVEMT ^N L SKPKKLAD ^D DNVHL KLFADD YIVKRKKLADD YIVKR ₀ K ^D DNVHL KKLAD T ^{N Y} KKKDNII ^Y F _Q VIRKT _G ^I K ^N F _Q VIRKT _G ^I K I KK H _G ^E KI O M _{G G G} Y N F R F H I ^A K G M _G ^N _G ^N _G N Y Y D R T Y L M _G ^N _{G G} ^Y N Y Y D R T Y L M ^N E H _G ^E G A ^Y F G N Y I ^Q K S V N _G ^R R M _G ^N _G ^{N Y} F G N Y I _S ^Q V N ^R K G R ₆ ^W

0 ^{5 0} _{1 7} ^{. .} _{7 5} ⁷ 6 _{7 8 9 0} ⁹ ₉ 4 ^{4 4 5} ₁ ⁸

1 _{8 2 2 2 2 B 7} ⁴

L FLLE _S ^Y K L YFLLEP LE _S ^Y L ^H Y GDTE VK _G ^V _S ^P D L _G ^H NTE VK _G ^VP K LHYFL LE _S ^{Y H} YFLLE ^Y SD L _G ^P K L SD L ^H YFL GNTE ^VP K L _{S G S} D L _G NTE VK _G ^VP K SD NR ^{D D R} N _S VMLDV NR ^D VK ^V SVMLDV NR ^D VK SVMLDV NR N _S ^D VMLDV KF _{G Q} YYIKLFY KF ^D N _S ^D VMLDV N ^G NTE G _{G Q} ^R YYIKLFY KF _G ^{D R} N QYYIKLFY KF _G ^{D R} N QYYIKLFY KF _G ^D _Q ^R YYIKLFY KKIKVNNRA D KK NNRA K KVNNRA II RTKEV ^G L II ^I KVNNRA D KK KV QRTEEV ^G L II _Q ^I RTKEV ^G D K GL II _Q ^I RTKEV ^G D KK VNNRA HM _G ^K LFL V ^K _{G G} YH ALFL ^K _G H IALFL V _G ^K YH IALFL ^K _G L II ^I K QRTKEV ^G D H _G YH FL ^K _G L GYH SHLFKR _Q ^P DIKK ^H I SHLFKR ^P V _G Y QDIKK _S HLFKR _Q ^P NIKK _S ^H HLFKR ^P V QDIKK ^H IAL SHLFKR ^P V QNIKK KALDEK LDEK P KALDEK KP KALDEK G ^K VKP KA SATE DLVEYR ^H VK G _S ^K ATE DLVEYR _G ^{H K} V SATE DLVEY ^{H K} VKP KALDEK VKP DLEEYR ^H R _{G S} ATE DLVEYR _G ^H _S ^K ATE TAERLIMPNDD TAERLIMPNDD TAERLIMPNDD TAERLIMPNDD TAERLIMPNDD NLLE MIVLWV LE IVLWV LE MIVLWV LLE MIVLWV GYDI _S ^L EKDYYKD ^N L GYEI ^L M SEKDYYKD ^N L GYEI _S ^L EKDYYK _G ^N YEI _S ^L EKDYYKD ^N LLE GYEI ^L MIVLWV SEKDYYKD LVEKHRV EKHRV AFH LVEKHRV FH VEKHRV AFH LVEKHRV AFH VLEDKDL ^D AFH LV SDKI _G ^G VLEDKDL _S ^D DKI _G ^G VLEDKDL ^D A SDKI ^G L G VLEDKDL _S ^D DKI _G ^G VLEDKDL _S ^D DKI _G ^G KRYLPEE YLPEE HKNL KRYLPEE KNL KRYLPEE KNL KRYLPEE HKNL MLTFLFD ^K HKNLKR GATK MLTFLFD _G ^K ATK MLIFLFD ^K H GATK LIFLFD ^K H GATKKMLIFLFD _G ^K ATK KDDYVLVRHKA _S ^K KDD LVRHKA ^K M S KDD LVRHKAN KDD VLVRHKA _S ^K KA D NHRHLKT ^Y VLVRHKA _S ^K KDD K ^K TI TINHRHL KT ^Y V G TINHRHL KT ^Y AK _S EYPYDAK ^K _G INHRHL KT ^Y V S ^K T LKEYPYD AK _S ^{K K} LKEYPYD AK ^K _{G S} ^K TINHRHL QLKEYPYD PE ^S _Q LK GNTLKDILIPE ^N _Q LKEYPYD AK ^K _{G S} ^K LKDILI PE ^S _{Q G} NTLKDILI PE ^S NTLKDILI V ^F APL ^F _G NTLKDILI PE ^S _{Q Q} EPL LRVP ^F _G NT QEPL K ^T _{Q S} LILV _Q ^{S S} NLLRVP SIK TKNLILV ^S NL Q _S ^S IK ^S LLRVP _Q ^F EPL LLRVP ^F _{G Q} EPL NLLR Q ^S N SIK NLILV _Q ^{S S} N SIK YDK TE ^T EYDPKYILTE ^T T KNLILV GE YDPKYILTE ^T T K ^T T KNLILV _Q ^S _S ^S IK DAA ^K YIL SLD LR ^D _{G S} LYDAANLD LY DAANLD ^D _G E YDPKYILTE ^D _G E YDPKYILTE ^T T GE R _S ^D DLDLDE _G ^I VV LDE ^I L GVV H DLKLDE ^I LR _S LY DAANLD LR _S LY DAANLD R _S ^D LY GVV LKLDE _G ^I VV TH TYLKRK ^D H GN ^L DLK GT KRK ^N H GN ^L D G T ^N H LKLDE ^I L GVV H GN ^L D G T YLKRK _G ^N N ^{L E} _G VK _S NNIKNYKPTV ^Y E QE ^L YLKRK _G ^N N _G ^L T E YL GNIKNYKPT V _Q ^Y E _G ^L NIKNYKPT V ^Y E LKRK QE ^L Y GNIKNYKPT V ^Y E QE _G ^L NIKNYKPT VRLKTKIDLPLIVRLKTKIDLPLI VRLKTKIDLPLI VRLKTKIDLPLI VRLKTKIDLPLI ALKLMEA ^I ELV LMEA ELV ALELMEA ELV LELMEA LV WHFYRNP _S F ^S ALE Q HFYRNP _S ^I F I _Q ^S FYRNP _S ^I F ^S A ^S ALELMEA ELV GYNKN NE ^I I SEH _G ^W YHKN EH ^W H GYHKN ^I I _Q HFYRNP ^I E SF ^I I _Q HFYRNP _S ^I F I _Q ^{S S} NE _S EH _G ^W YHKN _S EH _G ^W YHKN E _S ^I EH VITYI ^K E _S ^I S _G ^S DKE I IKYI _S ^KS N GDKE _G DKE IKYI ^K NE S _G ^S DKE STKFFNAKR ^N L _S ^V TKFFNAKR ^N I KYI _S ^K GL ^V I STKFFNAKR ^N I TKFFNAKR ^N I IKYI _S ^KS N GDKE NPFEADIIF ^K _{G S} TNPFAADIIF _S ^{K D N} F _Q ^K A FD ^K T NPFAADIIF ^K _G L _S ^V S ^K _G L _S ^V TKFFNAKR ^N I GL KT NPFAADIIF _S T NPFAADIIF _S ^{K T} FN F G ^D EL ^{K N} F _Q A _Q A FD L ^K T QVF _{S S} N _G ^T N ^E EL _Q A D QAF ^D F S ^N F S LN ^T F GN ^E EL ^D F S _S LN ^T FD F GN ^E EL F VF _S ^{D N} I _Q ^K _Q ^P K _Q ^A V ^G L GELIE _Q ^A N DV _Q ^A V _G ^G EL IE ^A _Q VF QN V _Q ^A V _G ^G EL IE ^A _{Q Q} N DV ^A _{S Q} V ^G LN _G ^T N ^E E QVF ^D F S ^N F _Q A S LN GEL IE _Q ^A N DV _Q ^A V _G ^G EL DH ^S DV L ^V _S K PL IDH T _S ^S K PL RI DH ^S D ^{S V N} T _S K ^V PL RI DH K L LY _{G G} ED _Q ^V I ^T R Q E Y _G ^N I ^T _Q I ^{T N} T _S ^S K PL G D _Q ^V I ^T RI DH ^N T _{S Q} E Y _G D ^V P QI ^T RI GA ^K ED _Q LNKLNI _S ^N E _S ^A T _G ^L KV _G KLNI ^N _{Q S} E ^A E _G ED ST ^L Y GKV _G ^K KLNI ^N _{Q S} E ^A E ^L Y ST _G KV ^K E GKLNI _S ^N E _S ^A T _G ^L KV ^K E GKLNI ^N _{Q S} E ^A E ST ID _S EDILHKEA DDILHKEA IDDILHKEA IDDILHKEA VIDDILHKEA SELIVKNDLVL ^T VI S _S ^I ELIVKNDLVL _S ^{T I} V SELIVKNDLVL _S ^{T I} V SELIVKNDLVL _S ^T _S ^I ELIVKNDLVL _S ^T YEA ^Y IRDITKLTYEK DITKLT YEK IRDITKLT YEK RDITKLT PAV _G ELTDVKRYPEL ^Y IRDITKLT YEK IR GELTDVKRY PEL _G ^Y ELTDVKRY PEL _G ^Y ELTDVKRY PEL ^Y I GELTDVKRY ⁰ KKLADD ^E YIVKRKLFADD YIVKRKLFADD FADD ^E YIVKRKLFADD YIVKR ₀ K ^E YIVKRKL NN FH _G ^Q KI ^R KK ^{E Y} FH _{G G} KI E FH _G I KK H _G ^E KI O M _G R _G ^Y N Y I _S V N _G R M ^N E G A _G N Y I ^Q KI S V N ^R KK E FH G R M _G ^N A _G ^Y N Y I _S ^Q V N ^R KK G R M _G ^N A _G ^Y N Y I ^Q K S V N _G ^R R M ^N E G A ^Y F G N Y I _S ^Q V N ^R K G R ₆ ^W

0 ^{5 0} _{1 7} ^{. .} _{7 5} ⁷ 1 _{2 3 4 5} ⁹ ₉ 5 ^{5 5 5} ₁ ⁸

1 _{8 2 2 2 2 B 7} ⁴

L FLLE _S ^Y K L YFLLE _S ^{Y VP} K L LE _S ^Y L YFLLE _S ^Y LLE _S ^Y L ^H Y GNTE VK _G ^V _S ^P D L _G ^H NTE VK _{G S} D L ^H YFL GNTE VK _G ^VP K SD L _G ^H NTE _G ^VP K L YF SD L _G ^H NTE VK _G ^VP K SD NR ^D VMLDV NR _S VMLDV NR ^D _S VMLDV NR ^D VK SVMLDV NR N _S ^D VMLDV KF _G ^{D R} N _{S Q} YYIKLFY KF ^D N ^D G _Q ^R YYIKLFY KF _G ^{D R} N QYYIKLFY KF _G ^{D R} N QYYIKLFY KF _G ^D _Q ^R YYIKLFY KK KVNNRA D KK NNRA K KVNNRA II _Q ^I RTKEV ^G L II ^I KVNNRA D KK KV QRTKEV ^G L II _Q ^I RTKEV ^G D K GL II _Q ^I RTEEV ^G D KK VNNRA HIALFL V ^K _{G G} YH ALFL ^K _G H IALFL V _G ^K YH IALFL ^K _G L II ^I K QRTKEV ^G D P _G YH FL ^K _G L GYH SHLFKR _Q DIKK ^H I SHLFKR ^P V _G Y QDIKK _S ^H HLFKR _Q ^P DIKK _S ^H HLFKR ^P V QDIKK ^H IAL SHLFKR ^P V QDIKK KALDEK LDEK P KALDEK KP KALDEK ^{H K} VKP KALDEK VKP DLVEYR _G ^{H K} VKP KA SATE DLVEYR ^H VK G _S ^K ATE DLVEYR _G ^{H K} V SATE DLVEYR _{G S} ATE DLVEYR _G ^H _S ^K ATE TAERLIMPNDD TAERLIMPNDD TAERLIMPNDD TAERLIMPNDD TAERLIMPNDD NLLE MIVLWV LE IVLWV LE MIVLWV LLE MIVLWV GYEI _S ^L EKDYYKD ^N L GYEI ^L M SEKDYYKD ^N L GYEI _S ^L EKDYYKD _G ^N YEI _S ^L EKDYYKD ^N LLE GYEI ^L MIVLWV SEKDYYKD LVEKHRV EKHRV AFH LVEKHRV FH VEKHRV AFH LVEKHRV AFH VLEDKDL ^D AFH LV SDKI _G ^G VLEDKDL _S ^D DKI _G ^G VLEDKDL ^D A SDKI ^G L G VLEDKDL _S ^D DKI _G ^G VLEDKDL _S ^D DKI _G ^G KRYLPEE YLPEE HKNL KRYLPEE KNL KRYLPEE HKNL KRYLPEE HKNL MLIFLFD ^K HKNLKR GATK MLIFLFD _G ^K ATK MLIFLFD ^K H GATK LIFLFD _G ^K ATK MLIFLFD _G ^K ATK KDD RHKA _S ^K KDD LVRHKA ^K M S KDD LVRHKA _S ^K KDD VLVRHKA _S ^K KT ^Y VLV G NHRHLKT ^Y VLVRHKA _S ^K KDD K ^K TI TINHRHL KT ^Y V G TINHRHL KT ^Y AK _S EYPYDAK ^K _G INHRHL KT ^Y V S ^K T LKEYPYD AK _S ^{K K} LKEYPYD AK ^K _{G S} ^K TINHRHL QLKEYPYD PE ^S _Q LK GNTLKDILIPE ^S _Q LKEYPYD AK ^K _{G S} ^K LKDILI PE ^S _{Q G} NTLKDILI PE ^S NTLKDILI VP _Q ^F EPL ^F _G NTLKDILI PE ^S _{Q Q} EPL LRVP ^F _G NT QEPL KNLILV _Q ^{S S} NLLRVP SIK TKNLILV ^S NL Q _S ^S IK ^S LLRVP _Q ^F EPL LLRVP ^F _{G Q} EPL NLLR Q ^S N SIK NLILV _Q ^{S S} N SIK YDPKYILTE ^T EYDPKYILTE ^T T KNLILV GE YDPKYILTE ^T T K ^T T KNLILV _Q ^N _S ^S IK DAANLD LR ^Y _{G S} LYDAANLD LY DAANLD ^D _G E YDPKYILTE ^D _G E YDPKYILTE ^T T GE I R _S ^D DLKLDE _G VV LDE ^I L GVV H DLKLDE ^I LR _S LY DAANLD LR _S LY DAANLD R _S ^D LY GVV LKLDE _G ^I VV T RK ^N H GN ^L DLK GT KRK ^D H GN ^L D G T ^D H LKLDE ^I L GVV H GD ^L D G T YLKRK _G ^D N _G ^L V ^Y E QE ^L YLK GNIKNYKPTV ^Y E QE ^L YLKRK _G ^D N _G ^L T E YL GNIKNYKPT V _Q ^Y E _G ^L NIKNYKPT V ^Y E LKRK QE ^L Y GNIKNYKPT V ^Y E QE _G ^L NIKNYKPT VRLKTKIDLPLIVRLKTKIDLPLI VRLKTKIDLPLI VRLKTKIDLPLI VRLKTKIDLPLI ALELMEA ^I ELV LMEA ^I ELV ALELMEA ELV LELMEA ELV WHFYRNP _S F ^S ALE Q HFYRNL _S F GYHKN ^I I _Q ^S HFYRNL _S ^I F ^S A SF ^S ALELMEA ELV GYHKN ^KS NE ^I I SEH ^W EH ^W _G YHKN E ^I I _Q HFYRNP ^I SEH _G ^W YH ^I I _Q HFYRNL _S ^I F I ^{S W} _Q K ^S N KN _S EH _G YHKN E _S ^I EH VIKYI _{S G} DKE I IKYI _S ^KS NE _{S G} DKE YI _{S G} DKE I IKYI ^K NE S _G ^S DKE STKFFNAKR ^N L _S ^V TKFFNAKRK ^N I K GL ^V I STKFFNAKRK _G ^N L _S ^V TKFFNAKR ^N I IKYI _S ^KS N GDKE NPFAADIIF ^K _{G S} TNPFAADIIFF ^K T NPFAADIIFF ^K _G L _S ^V TKFFNAKRK ^N I GL KT NPFAADIIF _S T NPFAADIIFF TFD F GN ^E EL QVF _S ^{D N} F _Q ^K A FD ^E EL _Q A D QAF ^D F S ^N F LN ^T F GN ^E EL ^D F _Q A FD L F F _Q ^K A FD L ^K T T ^A _S N _G N _S ^N F S LN _G ^T N ^E E IE _Q ^A N DV _Q V ^G L GELIE _Q ^A N DV ^A _{S Q} V _G ^G EL IE ^A _Q AF QN V _Q ^A V _G ^G EL IE ^A _Q AF _S ^{D N T} N ^E E QA QN DV ^A _{S Q} V ^G LN _G F ^D F S ^N F _Q A A _S LN S _G EL IE _Q ^A N DV _Q V _G ^G EL DH ^N T _S K PL IDH T _S ^S K PL RI DH ^S D L ED _Q ^V I ^{T N} T _S K ^V PL RI DH ^{V L} Y _G I ^T R Q E Y _G ^N _Q I ^{T N} T _S ^S K PL G D _Q I ^T RI DH ^N T _S ^S K L Q E Y _G D ^V P QI ^T RI GKV ^K ED _Q ^V GKLNI _S ^N E _S ^A T _G KV _G ^K KLNI ^N _{Q S} E ^A E _G ED ST ^L Y GKV _G ^K KLNI ^N _{Q S} E ^A E ^L Y ST _G KV ^K E GKLNI _S ^N E _S ^A T _G ^L KV ^K E GKLNI ^N _{Q S} E ^A E ST IVIDDILHKEA DDILHKEA IDDILHKEA IDDILHKEA VIDDILHKEA SELIVKNDLVL ^T VI S _S ^I ELIVKNDLVL _S ^{T I} V SELIVKNDLVL _S ^{T I} V SELIVKNDLVL _S ^T _S ^I ELIVKNDLVL _S ^T YEK IRDITKLTYEK DITKLT YEK RDITKLT YEK RDITKLT PEL _G ^Y ELTDVKRYPEL ^Y IRDITKLT YEK IR GELTDVKRY PEL _G ^Y ELTDVKRY PEL ^Y I GELTDVKRY PEL ^Y I GELTDVKRY ⁰ KLFADD ^E YIVKRKLFADD YIVKRKLFADD FADD ^E YIVKRKLFADD YIVKR ₀ K ^E YIVKRKL NE FH _G ^Q KI ^R KK ^{E Y} FH _{G G} KI E FH _G I KK H _G ^E KI O M _G A _G ^Y N Y I _S V N _G R M ^N E G A _G N Y I ^Q KI S V N ^R KK E FH G R M _G ^N A _G ^Y N Y I _S ^Q V N ^R KK G R M _G ^N A _G ^Y N Y I ^Q K S V N _G ^R R M ^N E G A ^Y F G N Y I _S ^Q V N ^R K G R ₆ ^W

0 ^{5 0} _{1 7} ^{. .} _{7 5} ⁷ 6 _{7 8 9 0} ⁹ ₉ 5 ^{5 5 6} ₁ ⁸

1 _{8 2 2 2 2 B 7} ⁴

L FLLE _S ^Y K L YFLLE _S ^{Y VP} K L LE _S ^Y L ^H Y GNTE VK _G ^V _S ^P D L _G ^H NTE VK _{G S} D L ^H YFL GNTE ^P K L ^H YFLLE _S ^{Y V} K L YFLLEP NR ^D VMLDV NR ^D VK _G ^V _S D L _G DTE VK _{G S} ^P D L _G ^H DTE VK _G ^VP K SD SVMLDV NR _S VMLDV NR N _S ^D VMLDV NR N _S ^D VMLDV KF _G ^{D R} N _{S Q} YYIKLFY KF ^D N ^D G _Q ^R YYIKLFY KF _G ^{D R} N QYYIKLFY KF _G ^D _Q ^R YYIKLFY KF _G ^D _Q ^R YYIKLFY KK KVNNRA D KK NNRA KIKVNNRA II _Q ^I RTEEV ^G L II ^I KVNNRA D KK KV QRTEEV ^G L II _Q ^I RTEEV ^G D K GL II RTEEV ^G D KKIKVNNRA HIALFL V ^K _{G G} YH ALFL ^K _G H IALFL V _G ^K YH I _G ^K LFL ^K _G L II TEEV ^G D H _G YH ^K R FL ^K _G L GYH SHLFKR _Q ^P DIKK ^H I SHLFKR ^P V _G Y QDIKK _S HLFKR _Q ^P DIKK _S ^H HLFKR ^P V QDIKK ^H I _G L SHLFKR ^P V QDIKK KALDEK LDEK P KALDEK KP KALDEK G ^K VKP KA SATE DLVEYR ^H VK G _S ^K ATE DLVEYR _G ^{H E} V SATE DLEEY ^{H K} VKP KALDEK VKP DLVEYR ^H R _{G S} ATE DLEEYR _G ^H _S ^K ATE TAERLIMPNDD TAERLIMPNDD TAERLIMPNDD TAERLIMPNDD TAERLIMPNDD NLLE MIVLWV LE IVLWV LE MIVLWV LLE MIVLWV GYEI _S ^L EKDYYKD ^N L GYEI ^L M SEKDYYKD ^N L GYEI _S ^L EKDYYKD _G ^N YDI _S ^L EKDYYKD ^N LLE GYDI ^L MIVLWV SEKDYYKD LVEKHRV EKHRV AFH LVEKHRV FH VEKHRV AFH LVEKHRV AFH VLEDKDL ^D AFH LV SDKI _G ^G VLEDKDL _S ^D DKI _G ^G VLEDKDL ^D A SDKI ^G L G VLEDKDL _S ^D DKI _G ^G VLEDKDL _S ^D DKI _G ^G KRYLPEE YLPEE HKNL KRYLPEE KNL KRYLPEE HKNL KRYLPEE HKNL MLTFLFD ^K HKNLKR GATK MLTFLFD _G ^K ATK MLTFLFD ^K H GATK LTFLFD _G ^K ATK MLTFLFD _G ^K ATK KDD RHKA _S ^K KDD LVRHKA ^K M S KDD LVRHKA _S ^K KDD VLVRHKA _S ^K KV ^Y VLV G NHRHLKV ^Y VLVRHKA _S ^K KDD K ^K TI TINHRHL KV ^Y V G TINHRHL KV ^Y AK _S EYPYDAK ^K _G INHRHL KV ^Y V S ^K T LKEYPYD AK _S ^{K K} LKEYPYD AK ^K _{G S} ^K TINHRHL QLKEYPYD PE ^S _Q LK GNTLKDILIPE ^S _Q LKEYPYD AK ^K _{G S} ^K TLKDILI PE ^S _{Q G} NTLKDILI PE ^S NTLKDILI VP _Q ^L EPL ^L _G NTLKDILI PE ^S _{Q Q} EPL LRVP ^F _G N QEPL KNLILV _Q ^{S S} NLLRVP SIK TKNLILV ^S NL Q _S ^S IK ^S LLRVP _Q ^F EPL LLRVP ^F _{G Q} EPL NLLR Q ^S N SIK NLILV _Q ^{S S} N SIK YDPKYILTE ^T EYDPKYILTE ^T T KNLILV GE YDPKYILTE ^T T K ^T T KNLILV _Q ^S _S ^S IK DAANLD LR ^D _{G S} LYDAANLD ^D YILTE LY DAANLD ^D _G E YDPK ^D _G E YDPKYILTE ^T T GE S DLKLDE _G ^I VV LDE ^I LR GVV H DLKLDE ^I LR _S LY DAANLD LR _S LY DAANLD R _S ^D LY GVV LKLDE _G ^I VV T RK ^N H GN ^L DLK GT KRK ^N H GN ^L D G T ^N H LKLDE ^I L GVV H GN ^L D G T YLKRK _G ^N N _G ^L V ^Y E QE ^L YLK GNIKNYKPTV ^Y E QE ^L YLKRK _G ^N N _G ^L T E YL GNIKNYKPT V _Q ^Y E _G ^L NIKNYKPT V ^Y E LKRK QE ^L Y GNIKNYKPT V ^Y E QE _G ^L NIKNYKPT VRLKTKIDLPLIVRLKTKIDLPLI VRLKTKIDLPLI VRLKTKIDLPLI VRLKTKIDLPLI ALELMEA ^I ELV LMEA ELV ALELMEA ELV ALELMEA LV LMEA ELV WHFYRNP _S F ^S ALE Q ^W HFYRNP _S ^I F ^I I _Q ^S HFYRNP _S ^I F ^S _Q HFYRNP ^I E SF I ^S ALE Q HFYRNP _S ^I F I _Q ^S GYHKN ^KS NE ^I I SEH _G YHKN NE _S EH ^W _G YHKN ^I I SNE _S EH _G ^W YHKN ^I _S EH _G ^W YHKN E _S ^I EH VIKYI _{S G} DKE I IKYI _S ^KS _G DKE _G DKE IKYI ^K NE S _G ^S DKE STKFFNAKR ^N L _S ^V TKFFNAKR ^N I KYI _S ^K GL ^V I STKFFNAKR ^N I TKFFNAKR ^N I IKYI _S ^KS N GDKE NPFAADIIF ^K _{G S} ^K TNPFAADIIF _S ^K A FD ^K T NPFAADIIF ^K _G L _S ^V S T NPFAADIIF ^K _G L _S ^V TKFFNAKR ^N I GL S T NPFAADIIF _S ^{K T} FD F GN ^E EL QVF _S ^{D N} F _Q ^E EL _Q A D QVF ^D F S ^N F S LN ^T F _Q A FD L F F _Q ^K A ^T FD A _G N ^E EL ^D F F ^{K T} L ^K T S _S ^N LN _G N ^E E QAF _S ^{D N} N ^E E QA IE _Q ^A N DV ^A _S N _G ^T N QV ^G L GELIE _Q ^A N DV _Q V _G ^G EL IE ^A _Q AF QN V _Q ^A V _G ^G EL IE _Q ^A N DV ^A _{S Q} V ^G LN _G F ^D F S ^N F _Q A A _S LN S _G EL IE _Q ^A N DV _Q V _G ^G EL DH ^N T _S K PL IDH T _S ^S K PL RI DH ^S D L ED _Q ^V I ^{T N} T _S K ^V PL RI DH ^{V L} Y _G I ^T R Q E Y _G ^N _Q I ^{T N} T _S ^S K PL G D _Q I ^T RI DH ^N T _S ^S K L Q E Y _G D ^V P QI ^T RI GKV ^K ED _Q ^V GKLNI _S ^N E _S ^A T _G KV _G ^K KLNI ^N _{Q S} E ^A E _G ED ST ^L Y GKV _G ^K KLNI ^N _{Q S} E ^A E ^L Y ST _G KV ^K E GKLNI _S ^N E _S ^A T _G ^L KV ^K E GKLNI ^N _{Q S} E ^A E ST IVIDDILHKEA DDILHKEA IDDILHKEA IDDILHKEA ^{T I} VIDDILHKEA SELIVKNDLVL ^{T I} VI S _S ELIVKNDLVL _S ^{T I} V SELIV ^K NDLVL ^T V S _S ^I ELIV VL _{S S} ELIV YEK IRDITKLTYEK K I _C DITKLT YEK ^K NDL CDITKLT YEK ^K NDLVL _S ^T CDITKLT PEL _G ^Y ELTDVKRYPEL ^Y IRDITKLT YE GELTDVKRY PEL _G ^Y ELTDVKRY PEL ^Y I GELTDVKRY PEL ^Y I GELTDVKRY ⁰ KLFADD ^E YIVKRKLFADD YIVKRKLFADD FADD ^E YIVKRKLFADD YIVKR ₀ K ^E YIVKRKL NE FH _G ^Q KI ^R KK ^{E Y} FH _{G G} KI E FH _G I KK H _G ^E KI O M _G A _G ^Y N Y I _S V N _G R M ^N E G A _G N Y I ^Q KI S V N ^R KK E FH G R M _G ^N A _G ^Y N Y I _S ^Q V N ^R KK G R M _G ^N A _G ^Y N Y I ^Q K S V N _G ^R R M ^N E G A ^Y F G N Y I _S ^Q V N ^R K G R ₆ ^W

0 ^{5 0} _{1 7} ^{. .} _{7 5} ⁷ 1 _{2 3 4 5} ⁹ ₉ 6 ^{6 6 6} ₁ ⁸

1 _{8 2 2 2 2 B 7} ⁴

L FLLE _S ^Y K L YFLLE _S ^{Y VP} K L LE _S ^Y L YFLLE _S ^Y LLE _S ^Y L ^H Y GNTE VK _G ^V _S ^P D L _G ^H NTE VK _{G S} D L ^H YFL GNTE VK _G ^VP K SD L _G ^H NTE _G ^VP K L YF SD L _G ^H NTE VK _G ^VP K SD NR ^D VMLDV NR _S VMLDV NR ^D _S VMLDV NR ^D VK SVMLDV NR N _S ^D VMLDV KF _G ^{D R} N _{S Q} YYIKLFY KF ^D N ^D G _Q ^R YYIKLFY KF _G ^{D R} N QYYIKLFY KF _G ^{D R} N QYYIKLFY KF _G ^D _Q ^R YYIKLFY KK KVNNRA D KK NNRA K KVNNRA II _Q ^I RTEEV ^G L II ^I KVNNRA D KK KV QRTEEV ^G L II _Q ^I RTEEV ^G D K GL II _Q ^I RTEEV ^G D KK VNNRA HIALFL V ^K _{G G} YH ALFL ^K _G H IALFL V _G ^K YH IALFL ^K _G L II ^I K QRTEEV ^G D P _G YH FL ^K _G L GYH SHLFKR _Q DIKK ^H I SHLFKR ^P V _G Y QDIKK _S ^H HLFKR _Q ^P DIKK _S ^H HLFKR ^P V QDIKK ^H IAL SHLFKR ^P V QDIKK KALDEK LDEK P KALDEK KP KALDEK ^{H K} VKP KALDEK VKP DLVEYR _G ^{H K} VKP KA SATE DLVEYR ^H VK G _S ^K ATE DLVEYR _G ^{H K} V SATE DLVEYR _{G S} ATE DLVEYR _G ^H _S ^K ATE TAERLIMPNDD TAERLIMPNDD TAERLIMPNDD TAERLIMPNDD TAERLIMPNDD NLLE MIVLWV LE IVLWV LE MIVLWV LLE MIVLWV GYEI _S ^L EKDYYKD ^N L GYEI ^L M SEKDYYKD ^N L GYEI _S ^L EKDYYKD _G ^N YEI _S ^L EKDYYKD ^N LLE GYEI ^L MIVLWV SEKDYYKD LVEKHRV EKHRV AFH LVEKHRV FH VEKHRV AFH LVEKHRV AFH VLEDKDL ^D AFH LV SDKI _G ^G VLEDKDL _S ^D DKI _G ^G VLEDKDL ^D A SDKI ^G L G VLEDKDL _S ^D DKI _G ^G VLEDKDL _S ^D DKI _G ^G KRYLPEE YLPEE HKNL KRYLPEE KNL KRYLPEE HKNL KRYLPEE HKNL MLTFLFD ^K HKNLKR GATK MLTFLFD _G ^K ATK MLTFLFD ^K H GATK LTFLFD _G ^K ATK MLTFLFD _G ^K ATK KDD RHKA _S ^K KDD LVRHKA ^K M S KDD LVRHKA _S ^K KDD VLVRHKA _S ^K KV ^Y VLV G NHRHLKV ^Y VLVRHKA _S ^K KDD K ^K TI TINHRHL KT ^Y V G TINHRHL KT ^Y AK _S EYPYDAK ^K _G INHRHL KV ^Y V S ^K T LKEYPYD AK _S ^{K K} LKEYPYD AK ^K _{G S} ^K TINHRHL QLKEYPYD PE ^S _Q LK GNTLKDILIPE ^S _Q LKEYPYD AK ^K _{G S} ^K LKDILI PE ^S _{Q G} NTLKDILI PE ^S NTLKDILI VP _Q ^F EPL ^F _G NTLKDILI PE ^S _{Q Q} EPL LRVP ^F _G NT QEPL KNLILV _Q ^{S S} NLLRVP SIK TKNLILV ^S NL Q _S ^S IK ^S LLRVP _Q ^F EPL LLRVP ^F _{G Q} EPL NLLR Q ^S N SIK NLILV _Q ^{S S} N SIK YDPKYILTE ^T EYDPKYILTE ^T T KNLILV GE YDPKYILTE ^T T K ^T T KNLILV _Q ^S _S ^S IK DAANLD LR ^D _{G S} LYDAANLD LY DAANLD ^D _G E YDPKYILTE ^D _G E YDPKYILTE ^T T GE I R _S ^D DLKLDE _G VV LDE ^I L GVV H DLKLDE ^I LR _S LY DAANLD LR _S LY DAANLD R _S ^D LY GVV LKLDE _G ^I VV T RK ^N H GN ^L DLK GT KRK ^N H GN ^L D G T ^N H LKLDE ^I L GVV H GN ^L D G T YLKRK _G ^N N _G ^L V ^Y E QE ^L YLK GNIKNYKPTV ^Y E QE ^L YLKRK _G ^N N _G ^L T E YL GNIKNYKPT V _Q ^Y E _G ^L NIKNYKPT V ^Y E LKRK QE ^L Y GNIKNYKPT V ^Y E QE _G ^L NIKNYKPT VRLKTKIDLPLIVRLKTKIDLPLI VRLKTKIDLPLI VRLKTKIDLPLI VRLKTKIDLPLI ALELMEA ^I ELV LMEA ELV ALELMEA ELV ALELMEA LV LMEA ELV WHFYRNP _S F ^S ALE Q ^W HFYRNP _S ^I F ^I I _Q ^S HFYRNP _S ^I F ^S _Q HFYRNP ^I E SF I ^S ALE Q HFYRNP _S ^I F I _Q ^S GYHKN ^KS NE ^I I SEH _G YHKN NE _S EH ^W _G YHKN ^I I SNE _S EH _G ^W YHKN ^I _S EH _G ^W YHKN E _S ^I EH VIKYI _{S G} DKE I IKYI _S ^KS _G DKE _G DKE IKYI ^K NE S _G ^S DKE STKFFNAKR ^N L _S ^V TKFFNAKR ^N I KYI _S ^K GL ^V I STKFFNAKR ^N I TKFFNAKR ^N I IKYI _S ^KS N GDKE NPFAADIIF ^K _{G S} TNPFAADIIF _S ^{K K} T NPFAADIIF ^K _G L _S ^V S ^K _G L _S ^V TKFFNAKR ^N I GL KT NPFAADIIF _S T NPFAADIIF _S ^{K T} FD F GN ^E EL QAF _S ^{D N} F _Q ^K A FD ^E EL _Q A D QAF ^D F S ^N F LN ^T F GN ^E EL ^D F _Q A FD L F F _Q ^K A FD L ^K T T ^A _S N _G N _S ^N F S LN _G ^T N ^E E IE _Q ^A N DV _Q V ^G L GELIE _Q ^A N DV ^A _{S Q} V _G ^G EL IE ^A _Q AF QN V _Q ^A V _G ^G EL IE ^A _Q AF _S ^{D N T} N ^E E QA QN DV ^A _{S Q} V ^G LN _G F ^D F S ^N F _Q A A _S LN S _G EL IE _Q ^A N DV _Q V _G ^G EL DH ^N T _S K PL IDH T _S ^S K PL RI DH ^S D L ED _Q ^V I ^{T N} T _S K ^V PL RI DH ^{V L} Y _G I ^T R Q E Y _G ^N _Q I ^{T N} T _S ^S K PL G D _Q I ^T RI DH ^N T _S ^S K L Q E Y _G D ^V P QI ^T RI GKV ^K ED _Q ^V GKLNI _S ^N E _S ^A T _G KV _G ^K KLNI ^N _{Q S} E ^A E _G ED ST ^L Y GKV _G ^K KLNI ^N _{Q S} E ^A E ^L Y ST _G KV ^K E GKLNI _S ^N E _S ^A T _G ^L KV ^K E GKLNI ^N _{Q S} E ^A E ST IVIDDILHKEA DDILHKEA IDDILHKEA IDDILHKEA VIDDILHKEA SELIV DLVL ^T VI S _S ^I ELIV NDLVL _S ^{T I} V SELIV VL _S ^T _S ^I ELIV YEK I ^K N CDITKLTYEK ^K NDLVL _S ^{T I} V SELIV K I _C ^K DITKLT YEK ^K NDL CDITKLT YEK ^K NDLVL _S ^T CDITKLT PEL _G ^Y ELTDVKRYPEL ^Y I _C DITKLT YE GELTDVKRY PEL _G ^Y ELTDVKRY PEL ^Y I GELTDVKRY PEL ^Y I GELTDVKRY ⁰ KLFADD ^E YIVKRKLFADD YIVKRKLFADD FADD ^E YIVKRKLFADD YIVKR ₀ K ^E YIVKRKL NE FH _G ^Q KI ^R KK ^{E Y} FH _{G G} KI E FH _G I KK H _G ^E KI O M _G A _G ^Y N Y I _S V N _G R M ^N E G A _G N Y I ^Q KI S V N ^R KK E FH G R M _G ^N A _G ^Y N Y I _S ^Q V N ^R KK G R M _G ^N A _G ^Y N Y I ^Q K S V N _G ^R R M ^N E G A ^Y F G N Y I _S ^Q V N ^R K G R ₆ ^W

0 ^{5 0} _{1 7} ^{. .} _{7 5} ⁷ 6 _{7 8 9 0} ⁹ ₉ 6 ^{6 6 7} ₁ ⁸

1 _{8 2 2 2 2 B 7} ⁴

L FLDARL _C ^{L Y L} L YFLLE _S ^Y LE _S L YFLLE _S ^Y L ^H F GDTEFM I _G ^N V _G L _G ^H NTE VK _G ^VP K L SD L ^H YFL GNTE _G ^VP K SD L ^H _G NTE VK ^V _G ^P K I LFM YVF SD L _G ^{H Y} F QTELE _G ^Y NR E _Q ^K AKPTNR ^D VK R _S VMLDV NR N _S ^D VMLDV NR NHIK ^K TY D ^R NL _G KY _{G Q} YTIVKPLIKF ^D N _S ^D VMLDV NR G _Q YYIKLFY KF _G ^{D R} N QYYIKLFY KF _G ^D _Q ^R YYIKLFY KF _G ^D _Q ^R YAVML ^P K SK KKIKVDVVALV KK NNRA K KVNNRA II RA EV I _Q ^S II ^I KVNNRA QRTKEV ^G D KK KV GL II _Q ^I RTEEV ^G D E GL II _Q ^I RTEEV ^G D KK V IKIDR Y ^{I H} M _G ^Q LF _{Q S} ALFL ^K YH IALFL V _G ^K YH IALFL ^K _G L II ^I K QRT _Q ^Y AFL GYH TIALFD ^Q R QVK V SHLFTAE ^L V _S ^I EH SAE ^H I LFKR ^P V _{G Q} DIKK _S ^H HLFKR _Q ^P NIKK _S ^H HLFKR ^P V QDIKK KHLFTLPIA _G ^G D RALDELLPN ^N I _S H K _G LKALDEK ^K KP KALDEK KP KALDEK ^{H K} VKP RA ERLAVY DLNEY VL _S VEYR ^H V G _S ATE DLVEYR _G ^{H K} V SATE DLVEYR _{G S} ATE EV ^L D SEY VK _S ^E N TAERL ^R A Q NYF ^K TDL QATAERLIMPNDD TAERLIMPNDD TAERLIMPNDD TADRL _S ^K _G ^Y _S ^E AR DLLE K _G ^Y LE IVLWV LLE MIVLWV LLE MIVLWV IMPNT _G ^S _G ^E GYEI _S ^L IM ^D A LN SD _G ^G EL ^N L GYEI ^L M SEKDYYKD _G ^N YEI _S ^L EKDYYKD _G ^N YEI _S ^L EKDYYKD ^N LLD GYDI _S ^L MIVLDTL FIEKHMV EKHRV AFH EKHRV FH VEKHRV AFH LIDKHKKNYWL VLDDKEK ^K H KILV GA _Q ^T EDKDL _S ^D DKI ^G LV G VLEDKDL ^D A SDKI ^G L G VLEDKDL _S ^D DKI _G ^G VLALKKVDANE _S ^Q RRYLPRVRHV ^A VL S _S ^E KRYLPEE HKNL KRYLPEE KNL KRYLPEE HKNL KRYLPDLLDNHL MVTFLDLNHEAVMLIFLFD _G ^K ATK MLTFLFD ^K H GTTK LTFLFD _G ^K ATK MLTLLEE HKYD K YVEEDYRLTKDD _S KDD LVRHKA ^K M S KDD LVRHKA _S ^K KDDPVFD _G ^K ARHI K ^D D S ^K DKFDKNKLTKT ^Y VLVRHKA ^{K K} _G INHRHL KV ^Y V TINHRHL KV ^Y V G TINHRHL KAKEKLVRHPAR AK _{S S} ^K T LKEYPYD AK _S ^{K K} LKEYPYD T A ETINHIAT PE ^A EIV GETI ^S NKRYDK SIVRRPE ^S _Q LKEYPYD ^K _{G S} ^K TLKDILI PE ^S _{Q G} NTLKDILI P _Q ^{K S} NLK YLLE V ^F EPLKTEI ^R KVP ^F _G NTLKDILI ^A K SE ^S _{Q Q} EPL LRVP ^F _G N QEPL LLRVP _Q ^F EPL LLRVP ^L _{G Q} DPTI _G ^A HKYY K ^K _{Q S} LFLTILRN _G RKNLILV ^S NL Q _S ^S IK V _Q ^{S S} N SIK NLILV _Q ^{S S} N SIK YDP VV DYDPKYILTE ^T T KNLIL GE YDPKYILTE ^T T K DPKYILTE ^T T RNLLLLT N L DAA ^K YH SLV _Q ^S RK ^V N QEVDAANLD ^I LR _S ^D LY DAANLD ^D _G E Y ^D _G E YDKRYI ^Q I _S ^D F _G ^L D LDILNYPLDDLKLDE _G VV H DLKLDE ^I LR _S LY DAANLD ^I LR _S LY DVVALI ^Q _{S S} TD TT GVV LKLDE _G VV T ^L K QELYN D E YLKRK _G ^N N _G ^L T E YLKRK ^N H GN ^L D L _G T ^N H LDLDD R _G ^N MV GN ^L D G TE NE ^I L GVI Y VKENNE _G ^{I L Y} E ^K T E _G NIKNYKPT V _Q ^Y E _G ^L NIKNYKPT V ^Y E LKRK QE ^L Y GNIKNYKPT VK ^K I SPKIKKK _S ^K D _Q ^S VRLKTLK ^I _{G S} F _G V _Q ^Y SFL ^L FVRLKTKIDLPLI VRLKTKIDLPLI RLKTKIDLPLI VR KTIKNYLVH ALDIMIKDEV _S FALELMEA ELV ALELMEA LV ^V LELMEA LV WHFYREIDKKYK HFYRNP _S ^I F I _Q ^S FYRNP ^I E SF ^S _S ^S VL _G ^L LM ID GYHKHEAKRKKF _G ^W YHKN EH ^W H GYHKN ^I I _Q HFYRNP ^I E SF ^{K I} I _Q HFYK _Q A ^{L I} PI G _S LL SNE _S EH _G ^W YHKN _S EH _G ^W YNKENP _S ^I FEFT VIKYINPIFIPA IKYI _S ^KS NE _S ^I GDKE I _S ^K _G DKE IKYI ^K NE S _G ^S DKE STKFFK F FFNAKR ^N I KY GL ^V I STKFFNAKR ^N I TKFFNAKR ^N I IAYID EKLA NPFADP _G ^{S N} T A _S ^V TK A _S A _C ^L PNPFAADIIF _S ^{K K} T NPFAADIIF ^K _G L _S ^V S T NPFAADIIF ^K _G L _S ^V TKFFP ^S N GNKYEN S T NPFE NAKRF T D _Q VFL G _Q ^{F E} EDP Q DLPLDI ^A FD G _G ^T N ^E EL _Q A D QVF ^D F S ^N F S LN ^T F GN ^E EL ^D F F _Q ^K A FD L F F _Q ^K A N ^E E ^{I T} YNE _Q DLIF ^N L A _Q AF _S ^{D N} KP L ^G _G V IK _Q T _S ^A M I KNLIE ^A _{S S} ^N QN V _Q ^A V _G ^G EL IE ^A _Q AF QN V _Q ^A V ^G LN _G ^T GEL IE _Q ^A N DV ^A _{S Q} V ^G LN _{G G} EL IKT _S ^Q _S ^A F ^N F G ^D _{G S} ^K E QK DH ^N TRF _Q ^E I _S ^N EEADH T ^S D SK ^V PL RI DH ^S D NT _S K ^V PL H T _S ^S K PL LY _G HKKKT Y _G ^N _Q I ^T RI D Y _G ^N D _Q ^V I ^T RI DH VADV _Q ^S V _Q ^T L Q E LY _G ^L KLPLV ^T GEV ^K AEV GKK DLDRF _G ^L KV ^K ED _Q I ^T GKLNI ^N _{Q S} E ^A E _G ED ST ^L Y GKV _G ^K KLNI ^N _{Q S} E ^A E ST _G ^L KV ^K E GKLNI _S ^N E _S ^A T AA ^Q E GE ^E _S IKIDDD _Q ^V ITWVT VIDDILHKEA IDDILHKEA IDDILHKEA ^T IV _S ^L ED ^D DI Q I ^K E _S T ST SELIVKKDIANL _S ^I ELIVKNDLVL _S ^{T I} V SELIVKNDLVL ^T V S _S ^I ELIV VL _S TELIVI _S ^K HKK ^A Y SR Y K VTVYIIHLYEK DITKLT YEK ^K NDL Y _C DITKLT YDA IYDLKAK P _Q ^E L _G EID ^Y IRDITKLT YEK IR SK NPEL _G ELTDVKRY PEL _G ^Y ELTDVKRY PEL ^Y I GELTDVKRY PAI ^Y I GEKEITVLR ⁰ KLFAEKD _S V _G ^E _G ^Y IKLFADD YIVKRKLFADD RKLFADD YIVKRKLIAELTDIILD ₀ KT ^Y FH ^E YIVK E FLT ^L TTK ^{E Y} FH _{G G} KI E FH _G ^E I KKN L NRI O M A _{S G} N L K _Q R D N ^F K S M ^N E G A _G N Y I ^Q KI S V N ^R KK ^N E G R M _G A _G ^Y N Y I _S ^Q V N ^R KK G R M _G ^N A _G ^Y N Y I ^Q K S V N _G ^R R M A _G ^{N Y} F G N D _G ^KY I S H V R T ₆ ^W

0 ^{5 0} _{1 7} ^{. .} _{7 5} ⁷ 1 _{2 3 4 5} ⁹ ₉ 7 ^{7 7 7} ₁ ⁸

1 _{8 2 2 2 2 B 7} ⁴

I FLFM YVF I FIKLNE W L _G ^H _Q ^Y TELE _G ^Y Y L _G ^{H Y} FLFM VF W QTELE ^Y Y G TY L ^N ALY GLF ^N ALYFIKLNE W ALYFIKLNE NR IK ^K T G K NR K _G ^{K E} RT ^S A F _G LF T A F ^{N T} _G LF Q _Q VN _G F NR _Q ^K _Q ^{Q T} R QVN _S ^P F NR ^KQ RT Q _Q ^{T D R} NH VN ^P A SF KF _{G Q} YAVML ^P _{Q S} K KF ^{D R} NHI G _Q YAVML ^P K NRLN _Q ^K SK KYVE LPVADM KY ^L N SE ADM KY ^L N SE KK KV IKIDR KK RPEVFE KKEK ^Y PI C _Q ^L PEVLE KKEK ^{Y L} PIADM C _Q PEVLE II _Q ^I RT _Q ^{Y I} KV IKIDR KKEE _C ^Y QRT _Q ^Y FL E ILE TIALFD ^Q RAFL II QVK V TIALFD ^Q RA QVK ^I ILE N _G ^Y _S ^{L V} R C _G ^{G I} IDI ^L E SK ^Y L GP ^V R G _G ^{G I} ILE QIDI ^L E L SK _G ^Y P _G ^VG R G KHLFTLPIA _G ^G D KHLFTLPIA ^G V _Q ID ^M GD KHE ^I _{S Q} HIMPNY ^H _{Q S} KHEKHIMPNY _S ^N KHEKHIMPNY _S ^N RA DERLAVY M VLKE KAEAKM LKE KAEAKM LKE EV _S ^L EY ^E RA ^L DERLAVY KAENK Y ^E VK _S NEV _S EY K _S ^E N L IPR _G ^I NYII ^E L IPR ^V V SDYMI PR ^V V SDYMI TADRL _S ^K _{G S} AR DRL _S ^KY V G _S ^E AR ^E A _S ^Y FLKV PY _S A _S ^Y FLKV APY ^E L SA ^Y I SFLKV APY NLLD IMPNT ^{S E} TA G _G LD MPNT _G ^{S E} _{S G} LDYVDL ^D A GDDA LDYVDL _G ^D DDD VDL _G ^D DDD GYDI _S ^L MIVLDTL ^N L GYDI ^L I SMIVLDTL _G ^N YKDNEEKHW ^D YKDNEEKHW ^D LDY GYKDNEEKHW LIDKHKKNYWL LIDKHKKNYWL V FDEAD ^L _{G S} AV EFDEAN _S ^L AV EFDEAN _S ^L VLALKKVDANE _S ^Q VLALKKVDANE ^Q A S VL _C ^AA E GKVVRHA L _C ^A _G ^A KVVRHT IL _C ^A _G ^A KVVRHT KRYLPDLLDNHLKRYLPDLLDNHL KREEPTINHK ^K I G KREEPTI HK _G ^K KREEPTI HK _G ^K MLTLLEE TLLEE HKYD MLIVLLKAYR MLIILLK _G ^N YR MLIILLK _G ^N Y KDDPVFD ^K HKYDML GARHIKDDPVFD _G ^K ARHI KDDHYILADP _S ^D KD NYILADP _S ^D KD YILAD _S ^R _S ^D KAKEKLVRHPARKAKEKLVRHPARRATETK IA RA _S ^D ETK NIV RA ^D N SETK NIV T NHIATT A I _Q ^{S S} N SVL KKKLDV _Q ^S _S ^S VL KKKLDV _Q ^S _S ^S VL P ^K A Q ^S ETI L _G NLK P _Q ^{K S} ETINHIAT KKKLD ILAEK _C ^E VEETKILTDK _C ^E VEETKILTDK _C ^E VP _Q DPTI ^A YLLE GHKYYVP ^L _G NLK YLLE VDEMK QDPTI _G ^A HKYY L E LR R N L IMNN R N RNLLLLT LLLLT L ^S TKN SLKTE _G ^I VV ^S N L SK D ^S IMNN SLKTE ^I L GVV _S ^S A D _S ^S LKTE ^I L GVV _S ^S A YDKRYI ^Q N L RN SI _S ^D F _G ^L YDKRYI ^Q N I _S ^D F ^L D G NNMMLKRK NDMMLKLK AD MLKLK VD DVVALI _S ^Q TD TTDVVALI ^Q _{S S} TD TT _Q ^Y VFYKMKNY ^N AD GHD _Q ^Y VFYKMKNY _G ^N HD ^Y NDM QVFYKMKNY _G ^N HD DLDLDD LR _G ^N MVDLDLDD EID KYL DLPKEEID TE ^K INE _G ^I VI ^I LR _G ^N MVDLFKE TA ^L PLRTE YITA ^L KHL DLPKEEID QPLRTE ITA ^L KHL TE PLR VK _S PKIKKK ^K Y SD _Q ^S VK ^K INE _G VI Y TKKYI SPKIKKK _S ^K D _Q ^S LEKFFNP ^I _{Q S} NLKLE _Q ^K FFNP _S ^I NP ^I _{Q S} VR KTIKNYLVHVR L N _Q ^F ATRVRFDDV ^S N ^F KLKLE ^K Y QFF QIT RFDDV ^F KLK QIT VL _G ^L LM D ^L KTIKNYLVH ARFAD L ^I PIVL _G LM ID PI AL P _G ^S DKTMAAL P _G DKTV ^R V S AL VP ^S N GDKTV _S ^{R W} HFYK ^K I QA FYK _Q ^K A _G ^L _S ^I LL _G ^{N E} I Q DATRALE H _G ^{N A} V Q NATRALE H _G ^N _Q ^A GYNKENP ^I _{G S} LL H SFEFT _G ^W YNKENP _S ^I FEFT ^W H GYKK _S ^A DLIF YKK _S ^A DLIF ^A NATRALE VIAYID NEKLA IAYID LA LDF ^N HY _G ^W SN I T LDF ^K HY _G ^W YKK _S DLIF V _S N I ^K HY STKFFP _G ^S NKYEN _S TKFFP ^S NEK SNKYEN ^V I ST ^S T G _G ^K IA ^{Q S K} IA ^Q FP _G ^L _S ^V T NPFE NAKRF LNPFE AKRF ^S _S FP _G ^L _S ^V T _G ^S T G ^K LDF GIA ^Q _S N SFP _G ^{L E} V _Q V PV ^K _{G G} F ^S _S TYNE _Q ^I DLIF ^N V YNE ^I N QDLIF ^N L NRI _G ^K F QIPL ^E LT N GVI YIDD ^E V _Q V QIPL ^E LT NPV _G ^K F V _Q ^S V LT GVI GKP F ^G _G ^G _G V ^T YIED P A ^{T T} YIDD _Q ^E IPL _G ^E VI IKT ^Q L S _S ^A F _G ^{N D} _G ^K E _G ^T KP S ^{Q A} L SF ^N F G ^D _{G S} ^K E _G N QKIE ^L IV S K ^S V ^K N IVK I _S ^AK N IVK DH VADV ^S _S KIKT QV ^T _{Q Q} L VADV _Q ^S V _Q ^T L ^{Y V} _Q VA _{Q Q} ^MS _{G Q} IK _S ^L K ^S V Q _Q ^{Q S} _{G Q} IK _S ^L K ^S V QI _S ^A _Q ^K _Q ^Q _Q ^{S L} E _G IHKI Y DHI ^Y _G E ^I _{Q G} IHKI HI _G ^Y E _G ^I IHKI LY _G PLV ^T DH SLY _G ^{L T} DHI _G VDDLE _G ^N I Y AEVDDLE ^N Y D GI Y AEVDDLE ^N Y GI AA ^Q EKL L _G E I E _S ^E TAA ^Q EKLPLV GE DI ^E _{S S} T ^L Y GA ^F AE Q I KITT ^{L K} I _G E _Q ^F KKITT I _G ^L E _Q ^F IKKITT IV _S ED ^D D Q ^K I _S ^K T YIV _S ^L ED _Q ^{D K} E QDDVK _Q T IVA ^Y I GNLDDVK _Q ^K ELIVI ^K I _S T VA _G ^Y N ^K SHKK ^A Y I SRTEFDWLAYIKAATEFHWLAY ^T IVA _G ^Y NLDDVK ^K I Q TELIVI _S HKK _S ^A RT IKA _S TEFHWLAYIKA _S ^T YDA IIYDLKAKYDA PAI _G ^Y EKEITVLRPAI ^Y IIYDLKAKYELKPD GEKEITVLRPEDERH ^T VEN YE ^M KPDT VEN YE KPDT RVEN S ^N R S INL PE _G ERHT ^N R S INL PE _G ^M ERHT _S ^{N 0} KLIAELTDIILDKLIAELTDIILD KI ₀ KN INRIKN ^V L _Q ^V NAL KI TIY N N FL ^{Y Y} FL RI KT ^T VIY SD _Q NE E KT _S ^{A V} L _Q ^{V A} L KI TIY ^V INL VL _Q N Y NK ^A L SE O M A _{G G} N D _G ^K _S H V R T M A _G ^N _G N D ^KY IN G _S H V R T M A K N ^E T G T E H I ^M _{Q G} ^S K M A K _S ^N _G ^{E T} _Q NK S E H M ^M _S E KT _S ^A Q A K M A K _S ^N _G ^{E T} _{Q S} E H M _Q ^M A K ₆ ^W

0 ^{5 0} _{1 7} ^{. .} _{7 5} ⁷ 6 _{7 8 9 0} ⁹ ₉ 7 ^{7 7 8} ₁ ⁸

1 _{8 2 2 2 2 B 7} ⁴

W LYFI ALYFI E NR ^{D R} YAIV _G ^{T I} L W _G ^{D R} FNNR LV F ^H A GLF ^K LKE W K ^Q LF ^K LK G _Q VYNVV ^K Y _S L SK ^H YFLDVV GDTEAVVL _S ^K _S ^N F _G ^N I _Q VLKV _Q ^L II NR N _{Q Q} ^T _Q T D F _G ^H QVN _G ^S F NR ^K _Q ^T _Q T D KF QVN _G ^S F KKIKTKDEVL ^Q L R NY APYD NRIKTPPVPAY KY _S ^L E PIADL KY ^L N _Q ^{Q Y L} _S E PIADL IIERFAP ^G _Q N F _G ^D _Q ^R YK ^I D Q KID KFARF EYYE KKEE _{C Q} PEVFA KKEE _C ^Y _Q ^L PEVFA TIALMLN ^I A SN ^V _S I K SLL KKIKVAE _S ^E VVN _G ^G KKLLK ^L K Q IILE E LE R K LFER LPPVEDL EE _G ^{Y E} VAF SRVI QIDI _S ^L K ^Y L R GP _G ^V _G ^G H ^I I QIDI ^L E SK ^Y L LEA I RT GP _G ^V _G ^G H R _S ^H LDYK ^H P GVY ^I I M _G ^K LY VLLK ^I ILF SINNY MPLVE KHTKHIMPNYV KHTKHIMPNYV DLNDLEMNA ^K L _{G S} EN _S ^H HLFK ^R EV Q A HN KHE I _Q ^L IV KADAKM ^V VLKE KADAKM E TADR V F ALDEK ^K D G N _S ^P HL KAI _Q ^{E E} LYIPR _S NYII ^E LYIPR ^V VLK SNYII LD ^P I SLK ^D D SH ^N L K LEEYIM _S ^D LKAD EINE ^L AN _S ^{L P} R N _S F S _Q V SATFLKV ^D APY _S ATFLKV APY ^N L GYEIHKV ^A _G VD G AERLMV YPHI TAEIHIL ^D LDK SAFE DLDYVDL _G DDA DLDYVDL _G ^D DDA FIEKKEI ^K A GH ^K D T LLE EK _G ^K ANYR R E GYEDNEEKHW EDNEEKHW ERH ^S _{Q Q} F _S ^S _G ^N YDI _S ^P RVRDDLT ^N LEK GYYEP _S ^M D ^K V GV ^G K GN SV EAD ^L Y S _S ^G V ^L VLEAP DNYIET LVEKHDLNHDLE FVDILRVRAY IL _C ^AA EFD GKVVRHK ^A EFDEAD _S TRYLL _Q ^D C _G ^A KVVRHK VANENT VLEDKEEAAFDY VLDFVDI NK _Q ^N KRNEPTI ^E IL NEPTI HK ^E MLTFVF G KDDEKLV NT Y KRYLPFDKHL NR NEK _S ^N LKI MLIILLK ^N HK _G KR GYRD MLIILLK _G ^N YRD KAKDETK _Q ^K VK _S ^A RMLTFLLV H ^Q _{S Q} ^Y EFL YT KDDKYILADPI KDDKYILADPI A T LTEKAKKDDYVTI _S ^S Y ^G _{S G} ^L ML ^T GKT KD NV ^K AN _S ^Y RAKETK ETK A P _Q ^{K G} EL KKKLDV _Q ^{S S} NIA RAK SVLE KKKLDV ^S NI Q _S ^S VLE VD ^I _G PI QKLL ^S TRVLRKA DKLKTDN ^L Y QLLILD AK _S ^K TLLN ^K I ^K A _Q ^G LT ^S _{S Q} TDW VKETKILTEKY VKETKILTEKY KRLLYVLVKNR ^S YLLTH ^V I PE ^S E ^Q _{S S} KL _S IE IV A ^Q _{S Q} L AND LR K L AND K YDK ^R TI ^F _G NL VI _G V _Q D ^Q H SLKTE _G ^I VV _S ^N E D ^Q H SLKTE ^I LR GVV _S ^N E DAA _S DE ^I LY RT V IVH V _Q ^K _Q ^K DK ^I L GVHK _S ^D GN ^{V T} _Q APV _Q ^S RE SLILILNR _G DVKIK YDNMMLKLK N ^Y DNMMLKLK AN ELDLYEKD ^L _{Q G} P ^R E K GD YDK N DV ^T K ^D RHRN Q ^L I QL YDELIVKNLR QIFYKMKNY ^K A GHD _Q IFYKMKNY _G ^K HD ND K F NF DAA ^K Y SLE _G ^I E T DAETTEIDDI _G ^K DLHKEEID KEEID YL IK ^E INL SPTII _S ^I D _S ^Y EF DLDLDLK ^I K SYE _G ^N ADL MEA NLN TEKYITA ^F KYLDLH YITA ^F K QPLRVR ANKLLVTH TNIKNLVKE TY ^L T QKRL ^I IKI LKKFFNP ^V _Q PLRTEK S ^F NLKLKKFFNP _S ^V LKAL ^L K GI ^M E GAPDRVEF VK _S ^E NNEIDEKH VKFLET ^P _{S S} NE IV VRFDDL N _Q PA DDL ^F N AL ^S N _Q PA FYEN ^S KFKF RLKTAAKFKV _C ^M I R _S ^Q KE AVP _G ^S DKTM ^R VRF SAL ^A VP _G DKTM _S ^{R W} H GY _G I ^T V LKLMNPIEVEP ^V RVY SLKKF _Q ^{D G} D STV WH _G ^K _Q NATRVLE H _G ^K _Q NATRVLE ^N RIA SYFEAF ^D R SI ^L _S A SP HFYHE FKIKL AYLLK _G ^{E K} T SL GYTK _S ^A DLIF Y _G ^W YTK _S ^A DLIF HY ^V I STKF L VTY _G ^W YNKEP _G ^S N ^Y HKY VI T LEF ^N H T LDF ^N N PFD ^A D QDN _Q ^S IKK _G ^A ITYINA ^A R QF ^S L _G YFFVK ^E FYKHR ST _G ^S K _G ^K IA ^Q _S N ^L I K _G ^K IA ^Q _S AP P _S ^V TKFFDLP ^V _S Y ^V INE QAD _S T ^A E _S ^S L YV SDV _Q N _Q ^P LR NPV ^S _S FP _{G S} ^V T _G ^{S S} _S FP ^L N G YNE ^{S G} F _Q V TNPV ^G F _Q V LT _G ^T TP ^A L SFVI ^K F SDL _S ^L NPFE M I _S PWKNP ^G E QEADIPF LT TFI _S D ^E V QIPL ^E L GLI _S D ^E V QIPL _G ^E LI IKR _S ^Q AAAIKKKT FN ^A GDIIVK V ^T FI S _G DIIVK EHLVIF _G ^{T D} _Q F _Q ^S VV ^Y L NLEIT _S ^I EE SR _G ^K _G ^T _Q ^{F N} K GTEYEIKEMY IKN ^S I _S ^A _Q ^K _Q ^M _Q IKN ^S V ^A _Q ^KM _Q ^S DH TDTKLI I _Q ^KP _Q AVVHL QK DYV ^Y K GE ^M _{Q G} LHKI YDYV ^Y K I _{S Q} Y ^L VEK G ED GE ^M _{Q G} LHKI _G AL _G ^K DK IDLF DH ^S K D LKT IEV DP R L Y ^{L V} GI Y ^F AEVDDLE _G ^N I ^L I I _S ^N V HI _G ^K VH ^A H SDF _S ^{K L L} Y AEVDDLE ^{N I} RAEVI _S DIWKL ^L _G ^V _S D _{Q G} EKHDKK _G ^{I Y} D Q FLDVL ^H _{G G} A _Q ^{F Y} IKKITTKI _G ^L A _Q KKITTKI _S ELIVIEYKV ^L Y K ^L HKIDE ^Q I QD ^E F _G T S PI IVA _G NLDDVKH ^Y I GNLDDVKH EA R VV ^E N _G A QL ^L NKILYL SEDVD V _G ^{N K} _{G Q} III NDEYV _G ^G I TEFHWLTYIKA ^T IVA STEFHWLAYIKA _S ^T _S ^{Y Y} DK GKLK _S ^Q N IM ^I D SELIIK ^D T SVTIN TE _G ^Y MFK L YE PD KPD EN Y ^K L SLAFLILR _G ^E A L _S ^D LITDL YE _Q ^F ANKY _S ^{T K} I _Q ^S PE ^V K GERH _S ^{T N} RVENYE SVINLPE _G ^V ERH _S ^{T N} RV SVINL R ANAT ^D N QL ^Y E SAI _G ^Y _Q ^V LNRKIVKDDA WKPL ^A _{Q S} I ^L H QI ⁰ KVTTIY LTNALKVTTIY LTNAL K _G ^N _G ^{N Y} ND GWNKNLE ₀ K ^{Y A} KKLAD S K ^D DNVHL LF _G ^Y PL KE TTD ^E T _Q ^V NE ^{V M} EK D T _Q NE E KFFNPY Q _G N M ^T T G K D _G ^E A E H M ^M K RD ^Q H SDLV ^N F GV O M _G K D _G A E H M _{Q G} ^S N M I L K T T ^K IKT _{G Q} ^{N N} F _Q VIRKT ^I N G _Q D K N K E M _{G G G} ^Y N Y Y D R T Y L M ^{T I} N G _G K I L D I T K K A ₆ ^W

0 ^{5 0} _{1 7} ^{. .} _{7 5} ⁷ 1 _{2 3 4 5} ⁹ ₉ 8 ^{8 8 8} ₁ ⁸

1 _{8 2 2 2 2 B 7} ⁴

W LY IKLN ALY IKLN FIKLN F ^N A GLF ^{F E} W LF ^{F E} W ^N ALY ^E W ^N ALYFIKLN W ALYFIKLN NRLN ^K _{Q Q} E ^T RT ^P _S F _G ^N QVN _S F NRLN ^K _{Q Q} E ^T RT QVN ^P _S F _G LF SF NRLN _Q ^KQ RT _G LF T _G ^E F _G ^N LF Q _Q ^T VN ^P _S F SF NRLN _Q ^K _Q ^{Q T} R QVN _S ^P F NRLN ^K RT ^E Q _Q ^Q _Q ^T VN ^P _{S S} F KYAE PIADT KYAE PIADT KYTE KKEE _C ^Y _Q ^L PEVLE KKEE _C ^Y _Q ^L PEVLE KKEE _C ^{Y L} PIADT KYAEY PIADM KYTE QPEVLE KKEEY _Q ^L PEVLE KKEE ^Y PIADT C _Q ^L PEVLE IILE E LE E L ILE QIDI _S ^L K ^Y L ^VG R GP _{G G} H ^I I QIDI ^L E SK ^Y L GP _G ^VG R ^I ILE GH _Q IDI _S ^L K _G ^Y P _G ^VG R GH _Q ^I IDI ^L E SK ^Y L GP ^V R G _G ^{G I} ILE QIDI ^L E ^Y L SK _G P _G ^VG R GH KHEKHIMPNYA KHEKHIMPNYA KHEKHIMPNYA KHEKHIMPNY _S ^N KHEKHIMPNYA KAETKM ^I VLKE KAETKM ^I VLKE KAEAKM VLKE KAEAKM LKE KAEAKM LKE DL ^Y IPR _S DYMI R _S ^I DYMI L IPR ^I V SDYMI PP ^I V SDYMI SA _S FLKV APY ^D L SA ^Y IPR _S DYVI L SFLKV APY _S ^D A ^Y IP SFLKV PY _S ^D A _S ^Y FLKV APY ^D L SA ^Y I SFLKV APY NLDYVDL _G ^G DDK DYVDL _G ^G DDK DYVDL ^G A GDDK LDYVDL _G ^D DDD VDL _G ^G DDK GYKDNEEKHW ^N L KDNEEKHW ^N L EEKHW _G ^N YKDNEEKHW ^N LDY GYKDNEEKHW AV EAN ^L _G Y S AV ^L _G YKDN FDEAN _S ^L AV FDEAN _S ^L AV EFDEAN _S ^L VL _C ^AA EFD GKVVRHE ^A EFDEAN _S AV C _G ^A KVVRHE ^A VVRHE VL _C ^AA E GKVVRHE VL _C ^A _G ^S KVVRHE KREEPTI ^K VL EEPTI HK ^K VL _C ^S E GK G KREEPTI K _G ^K KREEPTI HK _G ^K KREEPTI HK _G ^K MLIVLLK ^N HK _G KR GYR IVLLK _G ^N YR LK ^N H GYR MLIILLK _G ^N YR MLIILLK _G ^N KDDNYILADP ^D ML S KDDNYILADP ^D MLIIL S KDDNYILADP _S ^D KDDNYILADP _S ^D KDDNYILA ^Y R GP _S ^D RATETK TETK A RATETK IA RATETK NIA RATETK NIA KKKLDV _Q ^{S S} NIA RA SVL KLDV ^S NI Q _S ^S VL V _Q ^{S S} N SVL KKKLDV _Q ^S _S ^S VL KKKLDV _Q ^S _S ^S VL VEETKILTEK ^E KK C VEETKILTEK ^E KKKLD C VEEIKILTEK _C ^E VEELKILTEK _C ^E VEEIKILTEK _C ^E L TND ^I LR N L VTND N L ITND LR R N L ND R N D ^S V SLKTE _G VV _S ^S K D _S ^S LKTE ^I LR GVV _S ^S K D _S ^S LKTE _G ^I VV ^S N L SK D ^S VTND L SLKTE _G ^I VV _S ^S K D ^S IT SLKTE ^I L GVV _S ^S K YNNLMLKLK AD NNLMLKLK AD DLMLKLK NDLMLKLK QVFYKIKNY _G ^N HD _Q ^Y VFYKIKNY _G ^N HD ^Y N QVFYKMKNY ^N AD GHD _Q ^Y VFYKMKNY ^N A _G ^Y NDLMLKLK AD GHD _Q VFYKMKNY _G ^N HD DLVKEEID VKEEID YL DLVKEEID KYL DLVKEEID KHL NLVKEEID TE YITA ^L KYLDL A ^L PLRTE YITA ^L PLRTK ITA ^L KYL QPLR LE _Q ^K FFNP ^I _Q PLRTE S K ^K YITA ^L K QPLRTE FFNP _S ^{I K} YIT P ^I _{Q S} K KLE _Q ^K FFNP ^I _{Q S} KLKLE ^K Y QFFNP _S ^I VRFDDL N _Q ^F I ^L KLE _{Q S} RFDDL ^F K ^L KLE _Q FFN AL ^S N _Q I _S VRFDDL ^S N _Q ^F I _S ^L RFDDL N _Q ^F ITRVRFDDL ^F K QI ^L K S VVP _G ^S DKTV ^R V SAL ^{R V} VP _G DKTV _S AL _G DKTV ^R V S AL P _G ^S DKTIAAL VP ^S N GDKTV _S ^{R W} H _G ^N _Q NATRALE H _G ^N _Q ATRALE ^{N V} VP G _Q ATRALE H _G ^{N V} V Q NATRALE H _G ^N _Q ^V GYKK _S ^A DLIF Y _G ^W YKK ^A N SDLIF HY ^W H GYKK ^A N SDLIF Y _G ^W YKK _S ^A ELIF ^A NATRALE VI T F ^K H T EF ^K H S I T LDF ^K YKK _S DLIF S ^Q Y _G ^W G I T ^K HY ST _G ^{N K} LD ^Q _S ^L I ^K LDF ^{K N} A ^Q F _S ^N _G ^L _S ^V T _G ^{S K} VA ^Q FK _G ^L _S ^V T _G ^{S K} LEF GIA ^Q _{S S} F _S ^N _G ^L NRV ^K _G IA _G ^V I ST ^S T G ^K L G _G F ^S _S F _S ^N _{G S} ^V T _G ^N QV TNRV ^K _G IA ^Q _{S S} F _S ^{L S} I GF V _Q V LT NRV _G ^K F V ^S _{S Q} V RV ^K _{G G} F ^S _S TYIDD ^E V QIPL ^E L GVI DD _Q ^E IPL _G ^E VI IPL ^E LT N GVI ^E LT NRV _G ^K F V _Q ^S V LT GN IVK V ^T YI L ^S IVK ^T YIDD _Q ^{E T} YIDD ^E V _Q V QIPL _G VI ^{E T} YIDD _Q IPL _G ^E VI IK _S I _S ^A _Q ^K _Q ^{L S} _G N QIK _S ^{L S} V S _Q ^KL _Q ^S _G N Q IK ^L IVK S K ^S V N IVK QI _S ^A _Q ^K _Q ^{L S} _{G Q} IK _S ^{L S} V S ^K N IVK Q _Q ^{Q S} _{G Q} ID _S ^L K ^S V ^AK _Q ^L _Q ^S DHI ^Y K GE ^L _Q K _Q I ^{A A} GLHKI YDHI _G ^Y E _G ^L LHKI LHKI Y DHI ^Y K GE ^I _Q I _{S Q G} LHKI Y DHI _G ^Y E ^M _Q I GLHKI LY AEVDDLE _G ^N I Y AEVDDLE ^N Y DHI _G ^Y E _G ^M GI DDLE _G ^N I Y E _G ^N I Y AEVDDLE ^N Y GI GA _Q ^F ITT I _G ^L A _Q ^{F L} Y ^F AEV Y KITT I _G ^L A ^F AEVDDL Q KKIMT I _G ^L A _Q ^F KKITT IVA ^Y IKK GNLDDVK _Q ^K TIVA ^Y IKKITT GNLDDVK ^K I _G A _Q IK QT IVA _G NLDDVK _Q ^K T IVA ^Y I GNLDDVK _Q ^K T IVA ^Y I GNLDDVK ^K I QT TEFDWLTYIKA DWLTYIKA TEFDWLTYIKA FDWLTYIKA EFDWLTYIKA YE IPD ^S TEF MIPD E _S ^S YE PE _G ^M ERH _S ^{T N} RVE _S YE S INLPE _G ERH _S ^{T N} RV S NL PE ^M IPD GARH ^{T N} RVE ^S TE S YE ^M IPD VE ^A T S YE IPD RVE _S ^S S _S ^V INL PE _G ARH _S ^{T N} R S INL PE _G ^M ARH _S ^T _S ^{N 0} NI IY L _Q ^V NALNI AIY QNE EKT _S ^T N T ^V L ^V I QNAL NI ₀ KT ^T A SN _Q NE ^T AIY ^V L _Q N N ET ^V _Q NE ^A L NI SE KT ^T VIY L _Q ^V S T _Q ^V NE ^A L NI AIY ^V INL QN E O M A K N _G A E H M _Q ^I _S ^S K M A K N _G A E H M _Q ^{I S} E KT _{S S} K M A K _S ^{N E} T G A E H M _Q ^M A K M A K _S ^N _G ^E A E H M ^M _S E KT _S ^T NE ^A L SE Q A K M A K _S ^{N E} T ^V L Q _G A E H M _Q ^M A K ₆ ^W

0 ^{5 0} _{1 7} ^{. .} _{7 5} ⁷ 6 _{7 8 9 0} ⁹ ₉

8 ⁸ ₂ ⁸ ₂ ^{8 9 1} _{1 8}

2 _{2 B 7} ⁴

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W LYFI ALYFIKLN FI _S L F ^N A GLF ^K LN ^E W GLF ^E W ^N ALY ^K LN ^{S E} _G F ^{N K} FRDYAD IDLKT _Q ^T D TI NRLN _Q ^K _Q ^{Q T} _Q T _{G Q} ^S F ^N VN _G F NRLN _Q ^K _Q ^{Q T} RT QVN ^P _S F _G LF SF NRLN _Q ^KQ _Q T LMF REPDKK _G ^S Y _G ^K VE Q _Q ^T VN ^S _G W GF L ^H LF _Q KD GLNYMK _S ^P EKY NFAKFDI KYTE PIAEV KYAE PIADT KYTE KKEE _C ^Y _Q ^L PEVFA KKEE _C ^Y _Q ^L PEVLE KKEE _C ^{Y L} PIAEV NREEI LEA IMKLLRN ^{E L} KD S _S AF QPEVFA KYEN ^L MP QKVLEK RLTF IILE E LE ^L E L KLE _S ^L RRNKIH RNNP ^N KLTVY S _G ^I H QIDI _S ^L K ^Y L ^VG K GP _{G G} H ^I I QIDI ^L E SK ^Y L GP _G ^VG R ILE GH _Q ^I IDI _S K _G ^Y P _G ^VG K K GH VINIRKIDLYE TY VNV _G ^{G D} VH SLL KHEKHIMPNYA KHEKHIMPNYA KHEKHIMPNYA EMEAKRILA ^G V YT ^V Y GYIIERK KAETKM ^V VLKE KAEAKM ^I VLKE KAEAKM VLKE KHDEPME I _G I RDKKELEEV _S ^V _S ^{H D} L ^Y IPR _S NYII R _S ^V NYII KAYLLKD _G ^K SA _S FLKV APY ^D L SA ^Y IPP _S DYMI SFLKV APY ^D L SA ^Y IP SFLKV PY DLDFVRVR ^V YF RVV IKLAVYE GIK RLT _Q ^E K KK NLDYVDL _G ^D DNA DYVDL _G ^G DDK DL ^D A GDNA TAEYPDINNN AKLRE _S ^Q RT ^L AV SIF GYKDNEEKHL ^N L KDNEEKHW ^N LDYV EEKHL NLE ERVLP _S ^H TLIRELLLAIH AV EAN ^L _G Y S AV ^L _G YKDN FEEAN _S ^L YK ^E E GDFITYDT RF VL _C ^AA EFE GKVVRHT ^AA EFDEAN _S AV C _G KVVRHE ^A VVRHT _S ^G ILNPI ALE KL ^D I S ^S RNLPR S _G ^R EDD H KREEPTV ^E VL EEPTI HK ^K VL _C ^A E GK G KREEPTV K _G ^E ILDELT _Q ^S _S ^S DND LAL _S ^I L Y _G ^S K MLIVLLK ^N HK _G KR GYKD MLIILLK _G ^N YR LK ^N H GYKD KRL LYTHNE RNLKF _G ^WR F SKHFE KDDNYILADPI KDDNYILADP ^D MLIIL S KDDNYILADPI ILK ^E Y GTI LAKN RVILETNRK R RATETK ^{S S} NIA RATETK A RATETK IA KDIKDK _G ^I VHIY ADAEPYN Y _G ^G D KKKLDV _{Q S} VLE KKKLDV ^{S S} NI Q _S VL V _Q ^{S S} N SVLE KAD HPH ET KH ^Q VEETKILTEKR VEEIKILTEK ^E KKKLD C VEEIKILTEKR R ^L IKL SIKNYIK AN ^D N SLRR ^I _{S G} I ^D YE GKED L TND LR K L ITND N L ITND ^K D _Q ^R D ^S I SLKTE _G ^I VV _S ^S E D _S ^S LKTE ^I LR GVV _S ^S K D _S ^S LKTE ^I LR _Q EATEIDDRL T GVV ^S K V SE L KHE E ^Q LH SN ^M K YKK GK ^R A Q ^G VP ^{G Y} NDLMLKLK A _S NDLMLKLK AD DLMLKLK ^N LKLEA SNVNLP ^F N SVEYL DK _Q ^I ELT _S FD ^G _{G S} I QVFYKMKNY _G ^D HD _Q ^Y VFYKMKNY _G ^N HD ^Y N QVFYKMKNY ^D A _S T GHD LDFFEI NETVR _S ^G LAH NLVKEEID KEEID YL NLVKEEID RYL DAIKIE _G ^S DRKFL D ^A K EW TE YITA ^L RYLNLV YITA ^L K QPLRTE A ^L PLRDL YFDPTV ^D AP _Q K ^S K Q AN _S ^F _S ^K LE _Q ^K FFNP ^I _Q PLRTE S KLKLE _Q ^K FFNP _S ^{I K} YIT P ^I _{Q S} KLKKD _Q ^K FLELIK ^K ERF _G IIYLN _Q ^L ENTL SLT LEF K E LKYD VRFDDL N _Q ^F PT DDL ^F K ^L KLE _Q FFN AL ^S N _Q I _S VRFDDL ^S N _Q ^F PT KFDEDD PLE LIL _G ^S V _S ^I R _Q ^H KR VVP _G ^S DK ^R VRF SAL ^{R V} VP _G DKTV _S AL _G DK ^R I RNE KK ^F Y SF WH _G ^N _Q NATR ^N M QLE H _G ^N _Q ATRALE ^N VP G _Q ^V ATR ^N M _S V QLE ALA ^A EVRD ^R Y LDNKPAWPP ^R I N ^T _S R A _{S Q} FADTDM YIAT GYKK _S DLIF Y _G ^W YKK ^A N SDLIF HY ^W H GYKK ^A N SDLIF HK ^Q _{S S} KLIPFNP ^L _{G G} I LFE _S ^Y KLLE VI T F ^N H T DF ^N HY SN ^W Y TDLEIKILT M ^{H Y} F G _Q TE IKKKYY ST _G ^{S K} LD ^Q _S N ^L I ^K LDF ^{K N} A _S ^Q FP ^L _{G G} I _G ^N KKIKTYP NR N _S ^I VML L NRV ^K _G IA GF ^S _S FP _{G S} ^V T _G ^S QV TNRV ^K _G IA ^Q _{S S} F _{S G} ^{L V} I ST ^S T G ^K L GI GF V _Q ^S V LT NRV _G ^K F V _Q ^S V ^V V ^K I GDKIHRE F _G ^D _Q ^R YEIKL _S ^{D L T} YIDD ^E V QIPL ^E L GLI DD _Q ^E IPL ^{E E} LT _S T GVI IPL _G LI NPIDVMDDFK _Q ^MS K Q KK KVY GN IVK V ^T YI _Q M ^S _G N IVK ^T YIDD ^E IK _S ^{L S} I _S ^A _Q ^K _{Q Q} IK _S ^{L S} V ^L _G N ^S V ^M LIIDNI F F VI _Q ^I RT ^N NAD ^F _{G Q} T QI _S ^A _Q ^K _Q ^S Y Q _G ^T KT P D _S ^Q L _G ^N I IALF ^K _S V SPI ^T RII G Y DHI ^Y K GE ^I _{Q G} LHKI YDHI ^Y K _Q I _S ^A _Q ^K _{Q Q} ^S IK ^L IVK S K GE _G ^M LHKI LHKI L ^Y K GDI _Q ^V YT LY AEVDDLE _G ^N I Y AEVDDLE ^N Y DHI _G ^Y E _G ^I GI DDLE ^N Y ID ^T HLFML _S K _Q ^S GI DYFAF ^R V _{Q G} ^K EAV ^K QE RALDER VLNR GA _Q ^F ITTKI _G ^L A _Q ^{F L} Y ^F AEV KITTKI ^K N IVA ^Y IKK GNMDDVKH ^Y IKKITT GNLDDVK ^K I _G A _Q ^Y IK QT IVA _G NMDDVKH ^L Y ^I _S I ^T L Q _G ^Y N GWL L _S ^AK L LNEYK ^Y I GYA PI G ^S D G TADRLAMPN _S ^I TEFDWLAYIKV ^T IVA STEFDWLTYIKA TEFDWLAYIKV ^T _G N S IKFNPD _Q ^D E _G ^E W LLE IVVLE ^L L S YE IPD IPD E _S ^S YE PE _G ^M ARH _S ^{T N} RVENYE SVINLPE _G ^M ARH _S ^{T N} RV S NL PE ^M IPD GARH ^T RVEN TDLKKIA ^Q K GLE ^N YDL ^{L N} _S MKNY L _S ^T S _S VINL YE ^S TIYKILA _S ^KL _{G C} LIE KV A _S ^K EN ⁰ NI IY LPNALNI AIY L ^V I QN EV _S ^D DF ₀ KT ^T A S ^V LPNAL NK _Q AK KDN VLE ^K H SK ET _Q ^V NE EKT _S ^T N T _Q ^V NE ^A L NI M _S E KT ^T AIY S _Q NE RDE ^T RDV SILIKN R IPDE H ^N L GI O M A K _S ^N _G A E H M _Q ^M _G ^S K M A K N _G ^E A E H M _Q A K M A K _S ^{N E} T G A E H M _Q ^MS E KE G K M N K K E Y K D N I E ^T K S M L _S ^F L L E D _G ^K A _G ^G K E ₆ ^W

0 ^{5 0} _{1 7} ^{. .} _{7 5} ⁷ 1 _{2 3 4 5} ⁹ ₉

8 ⁹ ₂ ⁹ ₂ ^{9 9 1} _{1 8}

2 _{2 B 7} ⁴

L _G ^H ETE I _S ^F K _S ^P E W DNL _Q ^R PVKVI I AVKPY PY ETEDVVKHPL NR ^D IKLDV F _G ^H ITEYK L ^H ETET G ^R FMIAIL ^L I G L ^H ETEDVVK G KVIAIL ^L I G L _G ^H NKVIAAL KF _G ^{D R} N _{S Q} YYIMLFY NRMPNK ^K LV ^D _Q NR ^D N G _Q YFEEVLFT NR _G ^{D R} N QYY EVLFT NR _G ^D _Q ^R YY VLA _S ^T KKIKV EL E KYETFK ^Y _S LP GDA F KFIKVDV KKI KFIKVN _Q ^I KKI KFIKVN ^I E Q V LN II ^E RT ^K N QAHA _G ^G R KKE ^R I IPL _G ^{S N} KK V ^L V SA ^D M K RTEE ^L V SA ^{I D} M KK TEE _S ^L A _S EL SM _G LFLPV H II QHLFT V ^N Y GKE KM ^N _Q T _Q ^L IVAF _S II ^Q RTK GLFY ^S K I _G ^Q LFLPPN _S ^S SKYTADV F YILFKI ^I PN _{S Q} VL ^F _Q I G ILFKREVL ^F _Q II ^Q R GLFLPPNE KALDE ^R N Q EVKP KHKL IDV _G H EHLDEDEDY ^N _Q H Y GTI EHLDEK DY ^N _Q H YILFKREVL ^N V GE GTI EHLDEK Y _S ^K DLE RL ^K R QVLKAYE KANEYLP AHPL KANEYK _G ^Y HPL KANEYK ^Y D G AF ^K K Q TAE ^E YR _G ^H CLIM ^I VPE KA SANY ELLFYMEKNKN DLENIRE _S ^D DAL LENIIM ^D A SDAL DLENIIM _S ^D D L _S ^{T N} LLD MVPNWN MALNLEELLTV TALK GYDI _S ^P EKVL KD K VRYVY DI ^L K SK ^{Y K} HLA ^T D S TALK MV LA _S ^T TALK _{G G G} A IDI _S ^L EK ^K H GA ^L MV H ^G LVEKHRVDY _S ^Y E ^K L E _Q ^{E M} R SDINADD ^N L GYEKHIMRH ^I LN SEL _G ^N YEKHRVRH ^I LN _S EK _G ^K A ^E T GY SEL ^N LDI GYEKHRVRH _Q ^T VLEDKDL ^E _S Y LDYEKEDW VNHE IDEKDLNHE KRYLPEE ^D AN SDK ^I _G HV QLVLDIKFLKHN ^Y LVDEKM S VL KKY ^N VL GE VL LPEEKY ^N VLIDEKDLNHI ^A R SK MLTFLFD EKPI D RR ^Y LPE SFLRVAN _S ^K R _S ^Y FLFDAN ^K _G E VL PEEKYEAR S _S KRR ^Y L SFLFDADTLD KDD ^K HT GAK _S ^{Y K} PR SMIEALT ^T AN Q _S HKK ILDYVDL NF ^K KR Q LDNVLV F _Q ^K KA ^D VLV K _G KTIRHRHLKDYLVIWVHRY KDKEKEE _S ^S V L ^T M S KDK TI ^S N SV ^T MLDNVLV NKLV AK _S NHPYDKATMKI A _Q KAA DVE _G ^G AA ^E K SELKVE ^G L _S KDK KTI _S ^S VKRI G PE ^S ELK GE KYILIAKEPEK ^I LHK GVHII AK ^S EF VLR ^E T K GY AK DE ^E T KAA _S ^E ELKVEVRK V ^F NP ^T V Q ETVKKNLE _G ^V PE ^F _G EL Q PTIVI _Q ^T E _Q ^{F T} LLR Q VI ^T _G Y AK E LLRI Q RP ^F D P _Q ^T IN ^R D GF K ^K _{Q S} LILI _Q ^{S D} DLLRME SNKTTL ^K KRKI ^A RP SKVKL ^E P QLV _Q ^S RKI _S ^A KV ^E _{Q Q} L _Q ^E LV ^S V QRK NF YNKKYILRI ER ^T _{S S} ^S PIKNIKDD VKL _Q ^E LL GLDIDEDYWKKPKY LNYEARKKPKYILNYEARKKPKYILNY _Q ^V EK DAALLD TE ^D T SFYYD _Q ^I PYEA RPHL YDTTL _Q ^T DLDLDE _G ^I LR ^S DFTLD YDTTFD D TLD YDTTFD Q VKLVDAKLDE _G ^{I F} KLVDAKLDE ^I D G ^F PLF G EA TE VV _G ^E _Q ^RL DAI GDLK ^V TFP _S ^L VKND DAKLDV GDM AADLDLNIL _S ^I FKRI DLDLNLK ^I _{G S} FKRI DLDLNLK _S ^I F ^{Y E I} NIK _S FA IE _{S G} LTKRKKPTT TYE ^S HKE GDHKHMTEE ND VR KTKINYPIIV ^K V QELNEPV YRIKL _S ^K TE ^I DEVRKTEE VRKTEE GDKI L ^K N ST ^I KDE SIDKI D IKL ^K N ST ^I KDEL SIDKV ^L P S AL _Q ^L LMEADLLV ^S VREEIMII ^I T GNLR NLMLKKRN ^R D IK GF NLMEAKRN _G ^R F RNLMEAKRKY _G ^{A W} HFYRNP KMEA FVLR ^I R SLFYRIKIF NF ^I R SLFYRNPIF GYNKTA ^L E _Q ALD SF ^I L SEH HLK E _S ^F TT HKHLIF ^V _S LFYRNPIFRK EK YKHD F ^N NF ^I QEK HHKHD VITYIK _G ^S NEE I _G ^W YHL _Q ^R _Q ^P VR ^V T QEVE ^W H GYKYIEA ^N _Q P _S ^L SPLF ^W H GYKYIP _G ^{S N} PLF _G ^W YKYIP ^S F G ^N V STLT STKFFDPDK ^N L IFFIEVPRKLY KFFNP _Q ^A V EA KFFNA ^A _{S Q} V NKFEKDLKR ^K _{G S} T _S ^V T KFLEIFYK ^V I STFAAD ^{Y Y} EA IKFFNA _Q ^A VAIF SPL _S FA ^V I K ^L _S TFAADLPL _S FA _S ^V TFAADLPLFMT TFN IFF _Q ANP _Q ^A YKLLI E _G NPD _G I D L P NPD L I GK ^D ELD Q F FTELH ^Q F S PT F ^E ET AI ^N L SV ^L P NP P _S ^E EL I V _S ^L F ^E E Q F _G ^E I ^N HLF SKKL IK _Q E _S ^AF H SV ^{N G} LN ^T YK A _{S G} E D ^A I DV _G ^S LV _G ^T K ^A _{Q Q} N ^A N SDLHKKY _G ^{A T} F GK ^A _Q F _G ^E I _S ^N QN _S ^A DVHKKY _G ^A _G ^T K _Q ^A N _S ^A DVHKKDN DH ^L VKKV _Q V ^L _{G C} I ^N F QN ^A _S I _Q ^S IL I ^E DLRK IE RK E TKKVDLKDI LY _G PL ^T R Q EDY _Q KKD _Q ^{T S} IE ^N TKL GITVP _S ^L DH ^N TKKVDL G EDEITVP ^L I S DH _G ^N DEITDRI GE ^G EDN L _S KLAI E _S ^A T T _G ^A E Y _S ^S V ^F _Q DH _{G S} Y YV ^K EF GKDIDVTLT V _G ^K KLKDVTLT YV ^K E GKLKDVWIN IK _S EDIII _S ^N EA ^L Y _Q ^G TYT _S ^D VYIAIF ^L Y GDIEDILYIAIF _G ^L DIEDILYIANN SELILKDHKTL ^V _G A SLK _G ^{N E} KENI _G ^L YIED E KFIT LIVKN FIT KLIVKN ^Q KTLA YEA IRDDLKLTTEV ^K DYL _S LVAI KLIV _G ^K GIPTLTK K _S ^Q VHLF ^I K SEK LE ^Q K HLF _S ^I EK E _S V EKI _G ^Y DLVITKRYYEIDVKLRIK ^K T _S ^I EK Q ^Y LL LLKKKL Y L _G ^Y DL ^D _S V SLKKKL Y ^Y L L _S ^D LK _G ^KY L GE KLLADD DIVRRALLIDAEDIVL ^S Y _G DI Q P ^E L QFAEKNNRKDN P _Q ^E FAEDHNRKDN P ^E L _G D QFAEDHNRM D ⁰ K FH _G ^D YIIRKKLK KTI KLE FH KAI KLE H DIY _S ^K ₀ M _G ^{T N} K G _G ^Y NYI ^Y KLKIRI WKLE GNL ^D DI S T I ^Q KNKRNTL _G AEADIN _Q ^E I NTA ^Y F IRDRI NTA _G ^Y NY ^S DI GIRDRI NTA ^Y F GNY _G ^S IR ^V O M F F K W _S V V N D M P F A N L I L D V H E M A F D W D H D R W I N M A F D W T A D R W I N M A F D W T A D R ^R E _{S G} L I ₆ ^W

0 ^{5 0} _{1 7} ^{. .} _{7 5} ⁷ 6 _{7 8 9 0} ⁹ ₉ 9 ^{9 9 0} ₁ ⁸

1 _{8 2 2 2 3 B 7} ⁴

I TEDVVKPY I ETEDVVKPY I DVVKPY KPY I ETEDVVKPY L ^H E G IAIL _G ^L L _G ^H KVIAIL ^L I G L ^H ETEDVV G KVIAIL _G ^L L _G ^H NKVIAIL _G ^L NR _G ^{D R} NKV QYY EVLFTNR ^D NKVIAIL _G ^L L ^H ETE G _{G Q} ^R YY FT NR _G ^{D R} N QYY EVLFT NR _G ^{D R} N QYY VLFT NR _G ^D _Q ^R YY VLFT KFIKVN _Q ^I IKVN ^I EVL Q VKKI KFIKVN _Q ^I KKI KFIKVN ^I E Q VKKI KFIKVN ^I E Q VKKI KK RTEE ^L VKKIKF SA M EE ^L V SA K RTEE _S ^L A M KK TEE _S ^L A M II _G ^Q LFLPPN _S ^{D S} KK ^Q RTEE _S ^L A M GLFLPPN _S ^{D S} KK RT LPPN ^D M S ^S K I _G ^Q LFLPPN _S ^{D S} II ^Q R GLFLPPN _S ^{D S} YILFKREVL ^F _Q II QHYILFKREVL ^F _Q II _G ^Q LF QH YILFKREVL ^F _Q I ILFKREVL ^F _Q EHLDEK DY _G ^N TIEHLDEK TI EHLDEK DY ^N _Q H Y GTI EHLDEK DY ^N _Q H YILFKREVL ^F _{Q Q} H Y _G YK _G NEYK ^Y DY ^N G AHPL KANEYK ^Y _G TI EHLDEK Y _G ^N TI KANE _G HPL KANEYK _G ^Y HPL KANEYK ^Y D G AHPL DLENIIM ^D AHPLKA SDAL ENIIM _S ^D DAL DLENIIM ^D A SDAL LENIIM ^D A SDAL DLENIIM _S ^D DAL TALK MV ^T DL KHLA _S TALK V ^K HLA _S ^T TALK MV LA ^T D S TALK MV LA ^{T L} _S TALK NIDI _S EK _G A N DI ^L M SEK _G A LN DI _S ^L EK ^K H GA IDI _S ^L EK ^K H GA ^L MV HLA _S ^T GYEKHRVRH ^I L SEL ^N I GYEKHRVRH _S ^I EL ^N I GYEKHRVRH ^I LN SEL _G ^N YEKHRVRH ^I LN _S EK _G ^K A LN SEL ^N IDI GYEKHRVRH _S ^I EL LIDEKDLNHE VLIDEKDLNHE DLNHE IDEKDLNHE VL LPEEKY ^N EVL ^N VLIDEK EEKY ^N VL L SFLFDAN ^K _{G S} KRR ^Y LPEEKY _G E VL SFLFDAN _S ^{K Y} LP DAN ^K _G E V S KR ^Y LPEEKY ^N VLIDEKDLNHE RR ^Y R _S FLFDAN ^K _G E VL PEEKY ^N V GE S KRR ^Y L SFLFDAN _S ^K MLDNVLV F _Q ^K DNVLV NF ^K KRR _S FLF Q MLDNVLV F _Q ^K LDNVLV F _Q ^K KDK ^S N SV ^T ML SKDK KTI _S ^S V L _S ^T KDK KTI ^S N SV ^T M DK TI ^S N SV ^T MLDNVLV ^S NF ^K K Q KAA ^E KTI SELKVE ^G L G TKAA _S ^E ELKVE _G ^{G E} V L _S ^T ELKVE ^G L _S K G AA ^E K SELKVE ^G L _S KDK KTI _{S G} AK DE LR ^E YAK ^E T KAA _S T ^T LLR ^E T K AK DE ^E T KAA _S ^E ELKVE _G ^G PE _Q ^{F T} L VI ^T _{G Q} RPE ^F DE LLR _G Y AK Q _Q ^F DE Y AK E _G Y P _Q ^{T T} _G Y QRKI _S ^A KVKL ^E _Q LV ^S VI QRKI ^A RPE _Q P _Q ^S _Q RPE _Q ^{F T} LLR Q VI ^T _{G Q} RPE ^F D Q P ^T LLR ^E T Q I _Q ^T VKL ^E P _{Q Q} LV ^S _S KVKL ^E VI QLI _Q RKI _S ^A KVKL ^E P QLV _Q ^S RKI _S ^A KVKL _Q ^E LV ^S V QRKI ^A R SK KKPKYILNYEARKKPKYILNYEARKKPKYILNYEARKKPKYILNYEARKKPKYILNYEAR YDTTFD D TFD LD YDTTFD DAKLDE _G ^{I F} TLDYDT LDE ^I D G ^F T GKLVDAKLDE ^I D TLD YDTTFD D TLD YDTTFD G _G ^F KLVDAKLDE _G ^{I F} KLVDAKLDE ^I D G ^F TLD GKLV DLDLNLK ^I _G KLVDAK SFKRIDLDLNLK _S ^I FKRI DLDLNLK _S ^I FKRI DLDLNLK ^I _{G S} FKRI DLDLNLK _S ^I FKRI TEE DEVRKTEE KDEVRKTEE VRKTEE N KDEVRK IKL ^K N ST ^I K SIDKI DIKL ^K N KDEVRKTEE N ST _S ^I IDKI IDKI KL ^K N ST ^I KDE R _S IDKI D IKL _S ^K T _S ^I IDKI IRNLMEAKRN _G F RNLMEAKRN ^R D IKL _S ^K T _S ^I GF NLMEAKRN ^R D I GF RNLMEAKRN _G ^R F RNLMEAKRN ^R D GF SLFYRNPIF F _S ^I LFYRNPIF NF ^I R SLFYRNPIF ^N NF _S ^I LFYRNPIF ^N NF _S ^I LFYRNPIF WHYKHD F ^N N KHD ^N EK YKHD GYKYIP _G ^{S N} _Q EK HY ^S F EK HYKHD F _Q EK HYKHD ^N NF A _S PLF _G ^W YKYIP ^S F G ^N _Q LF ^W H GYKYIP _G ^N _{Q S} PLF _G ^W YKYIP _G ^{S N} PLF _G ^W YKYIP ^S F G ^N _Q EK SPLF VIKFFNA _Q V A IKFFNA ^A _S P QV EA KFFNA _Q ^A V EA IKFFNA ^A _{S Q} V S FAADLPL ^Y E SFA _S ^V AADLPL _S ^Y FA ^V I S FAADLPL _S ^Y FA _S ^{V Y} EA ^V IKFFNA _Q ^A V EA FAADLPL _S FA _S DLPL _S ^Y FA N _S ^T D ^{T E} EL I _S D L Q ^A F _G ^{E N} L PN ^T F L _S D ^E EL I I _S V _{S Q} F _G ^E I ^N L SV ^L P N _S ^T D ^E EL P N ^T FAA SD L I TF _S ^E I GI ^N L SV ^L P N S ^{N T} F ^E E ^E I L GI _S V _S ^L F ^E E Q F _G ^E I ^N L SV ^L P S _G K _Q ^A N _S DVHKKY ^{A T} F G _G K _Q ^A N _S ^A DVHKKY _G ^{A T} F GK ^A _{Q Q} N ^A F SDVHKKY _G ^A _G K ^A _Q F QN _S ^A DVHKKY _G ^A _G ^T K _Q ^A N _S ^A DVHKKY _G ^A IE KKVDLRK TKKVDLRK IE VDLRK IE RK E TKKVDLRK DH ^N T G EDEITVP ^L IE SDH _G ^{N K} EDEITVP _S ^L DH ^N TKK G EDEITVP _S ^L DH ^N TKKVDL G DEITVP ^L I S DH _G ^N DEITVP _S ^{L L} YV _G ^K KLKDVTLT YV _G KLKDVTLT V _G ^K KLKDVTLT V ^K E GKLKDVTLT YV ^K E GKLKDVTLT GDIEDILYIAIF _G ^L DIEDILYIAIF ^L Y GDIEDILYIAIF ^L Y GDIEDILYIAIF _G ^L DIEDILYIAIF IKLIVKN IVKN N SEK LE ^Q KFIT KL SVHLF _S ^I EK ^Q KFIT LIVK LE ^Q KFIT LIVKN FIT KLIVKN FIT LE _S VHLF ^I K SEK Y L _G ^Y DL _S ^D LKKKLY ^Y _G DL _S ^D LKKKL Y L _G ^Y DL ^D _S VHLF ^I K SEK LE ^Q K SVHLF _S ^I EK E ^Q K SVHLF SLKKKL Y L _G ^Y DL _S ^D LKKKL Y ^Y L L _S ^D LKKKL P _Q ^E FAEDHNRKDNP ^E L QFAEDHNRKDN P _Q ^E FAEDHNRKDN P _Q ^E FAEDHDRKDN P ^E L _G D QFAEDHNRKDN ⁰ KLE FH ^S DIKAIKLE H DIKAI KLE FH ₀ NTA _G ^Y NY _G IRDRINTA ^Y F GNY _G ^S IRDRI NTA _G ^Y NY ^S DIKAI KLE FH KAI KLE H DIKAI GIRDRI NTA _G ^Y NY ^S DI GIRDRI NTA ^Y F GNY _G ^S IRDRI O M A F D W T A D R W I N M A F D W T A D R W I N M A F D W T A D R W I N M A F D W T A D R W I N M A F D W T A D R W I N ₆ ^W

0 ^{5 0} _{1 7} ^{. .} _{7 5} ⁷ 1 _{2 3 4 5} ⁹ ₉ 0 ^{0 0 0} ₁ ⁸

1 _{8 3 3 3 3 B 7} ⁴

I TEDVVKPY I ETEDVVKPY I DVVKPY KPY I ETEDVVKPY L ^H E G IAIL _G ^L L _G ^H KVIAIL ^L I G L ^H ETEDVV G KVIAIL _G ^L L _G ^H NKVIAIL _G ^L NR _G ^{D R} NKV QYY EVLFTNR ^D NKVIAIL _G ^L L ^H ETE G _{G Q} ^R YY FT NR _G ^{D R} N QYY EVLFT NR _G ^{D R} N QYY VLFT NR _G ^D _Q ^R YY VLFT KFIKVN _Q ^I IKVN ^I EVL Q VKKI KFIKVN _Q ^I KKI KF KVN ^I E Q VKKI KFIKVN ^I E Q VKKI KK ^Q RTEE ^L VKKIKF SA M EE ^L V SA K _Q ^I RTEE _S ^L A M KK TEE _S ^L A M II _G LFLPPN _S ^{D S} KK ^Q RTEE _S ^L A M GLFLPPN _S ^{D S} KK RT LPPN ^D M S ^S K IRLFLPPN _S ^{D S} II ^Q R GLFLPPN _S ^{D S} YILFKREVL ^F _Q II QHYILFKREVL ^F _Q II _G ^Q LF QH YILFKREVL ^F _Q I ILFKREVL ^F _Q EHLDEK DY _G ^N TIEHLDEK TI EHLDEK DY ^N _Q H Y GTI EHLDEK DY ^N _Q H YILFKREVL ^F _{Q Q} H Y _G YK _G NEYK ^Y DY ^N G AHPL KANEYK ^Y _G TI EHLDEK Y _G ^N TI KANE _G HPL KANEYK _G ^Y HPL KANEYK ^Y D G AHPL DLENIIM ^D AHPLKA SDAL ENIIM _S ^D DAL DLENIIV ^D A SDAL LENIIM ^D A SDAL DLENIIM _S ^D DAL TALK MV ^T DL KHLA _S TALK V ^K HLA _S ^T TALK MV LA ^T D S TALK MV LA ^{T L} _S TALK NIDI _S EK _G A N DI ^L M SEK _G A LN DI _S ^L EK ^K H GA IDI _S ^L EK ^K H GA ^L MV HLA _S ^T GYEKHRVRH ^I L SEL ^N I GYEKHRVRH _S ^I EL ^N I GYEKHRVRH ^I LN SEL _G ^N YEKHRVRH ^I LN _S EK _G ^K A LN SEL ^N IDI GYEKHRVRH _S ^I EL LIDEKDLNHE VLIDEKDLNHE DLNHE IDEKDLNHE VL LPEEKY ^N EVL ^N VLIDEK EEKY ^N VL L SFLFDAN ^K _{G S} KRR ^Y LPEEKY _G E VL SFLFDAN _S ^{K Y} LP DAN ^K _G E V S KR ^Y LPEEKY ^N VLIDEKDLNHE RR ^Y R _S FLFDAN ^K _G E VL PEEKY ^N V GE S KRR ^Y L SFLFDAN _S ^K MLDNVLV F _Q ^K DNVLV NF ^K KRR _S FLF Q MLDNVLV F _Q ^K LDNVLV F _Q ^K KDK ^S N SV ^T ML SKDK KTI _S ^S V L _S ^T KDK KTI ^S N SV ^T M DK TI ^S N SV ^T MLDNVLV ^S NF ^K K Q KAA ^E KTI SELKVE ^G L G TKAA _S ^E ELKVE _G ^{G E} V L _S ^T ELKVE ^G L _S K G AA ^E K SELKVE ^G L _S KDK KTI _{S G} AK DE LR ^E YAK ^E T KAA _S T ^T LLR ^E T K AK DE ^E T KAA _S ^E ELKVE _G ^G PE _Q ^{F T} L VI ^T _{G Q} RPE ^F DE LLR _G Y AK Q _Q ^F DE Y AK E _G Y P _Q ^{T T} _G Y QRKI _S ^A KVKL ^E _Q LV ^S VI QRKI ^A RPE _Q P _Q ^S _Q RPE _Q ^{F T} LLR Q VI ^T _{G Q} RPE ^F D Q P ^T LLR ^E T Q I _Q ^T VKL ^E P _{Q Q} LV ^S _S KVKL ^E VI QLV _Q RKI _S ^A KVKL ^E P QLV _Q ^S RKI _S ^A KVKL _Q ^E LV ^S V QRKI ^A R SK KKPKYILNYEARKKPKYILNYEARKKPKYILNYEARKKPKYILNYEARKKPKYILNYEAR YDTTFD D TFD LD YDTTFD DAKLDE _G ^{I F} TLDYDT LDE ^I D G ^F T GKLVDAKLDE ^I D TLD YDTTFD D TLD YDTTFD G _G ^F KLVDAKLDE _G ^{I F} KLVDAKLDE ^I D G ^F TLD GKLV DLDLNLK ^I _G KLVDAK SFKRIDLDLNLK _S ^I FKRI DLDLNLK _S ^I FKRI DLDLNLK ^I _{G S} FKRI DLDLNLK _S ^I FKRI TEE DEVRKTEE KDEVRKTEE VRKTEE N KDEVRK IKL ^K N ST ^I K SIDKI DIKL ^K N KDEVRKTEE N ST _S ^I IDKI IDKI KL ^K N ST ^I KDE R _S IDKI D IKL _S ^K T _S ^I IDKI IRNLMEAKRN _G F RNLMEAKRN ^R D IKL _S ^K T _S ^I GF NLMEAKRN ^R D I GF RNLMEAKRN _G ^R F RNLMEAKRN ^R D GF SLFYRNPIF F _S ^I LFYRNPIF NF ^I R SLFYRNPIF ^N NF _S ^I LFYRNPIF ^N NF _S ^I LFYRNPIF WHYKHD F ^N N KHD ^N EK YKHD GYKYIP _G ^{S N} _Q EK HY ^S F EK HYKHD F _Q EK HYKHD ^N NF A _S PLF _G ^W YKYIP ^S F G ^N _Q LF ^W H GYKYIP _G ^N _{Q S} PLF _G ^W YKYIP _G ^{S N} PLF _G ^W YKYIP ^S F G ^N _Q EK SPLF VIKFFNA _Q V A IKFFNA ^A _S P QV EA KFFNA _Q ^A V EA IKFFNA ^A _{S Q} V S FAADLPL ^Y E SFA _S ^V AADLPL _S ^Y FA ^V I S FAADLPL _S ^Y FA _S ^{V Y} EA ^V IKFFNA _Q ^A V EA FAADLPL _S FA _S DLPL _S ^Y FA N _S ^T D ^{T E} EL I _S D L Q ^A F _G ^{E N} L PN ^T F L _S D ^E EL I I _S V _{S Q} F _G ^E I ^N L SV ^L P N _S ^T D ^E EL P N ^T FAA SD L I TF _S ^E I GI ^N L SV ^L P N S ^{N T} F ^E E ^E I L GI _S V _S ^L F ^E E Q F _G ^E I ^N L SV ^L P S _G K _Q ^A N _S DVHKKY ^{A T} F G _G K _Q ^A N _S ^A DVHKKY _G ^{A T} F GK ^A _{Q Q} N ^A F SDVHKKY _G ^A _G K ^A _Q F QN _S ^A DVHKKY _G ^A _G ^T K _Q ^A N _S ^A DVHKKY _G ^A IE KKVDLRK TKKVDLRK IE VDLRK IE RK E TKKVDLRK DH ^N T G EDEITVP ^L IE SDH _G ^{N K} EDEITVP _S ^L DH ^N TKK G EDEITVP _S ^L DH ^N TKKVDL G DEITVP ^L I S DH _G ^N DEITVP _S ^{L L} YV _G ^K KLKDVTLT YV _G KLKDVTLT V _G ^K KLKDVTLT V ^K E GKLKDVTLT YV ^K E GKLKDVTLT GDIEDILYIAIF _G ^L DIEDILYIAIF ^L Y GDIEDILYIAIF ^L Y GDIEDILYIAIF _G ^L DIEDILYIAIF IKLIVKN IVKN N SEK LE ^Q KFIT KL SVHLF _S ^I EK ^Q KFMT LIVK LE ^Q KFIT LIVKN FIT KLIVKN FIT LE _S VHLF ^I K SEK Y L _G ^Y DL _S ^D LKKKLY ^Y _G DL _S ^D LKKKL Y L _G ^Y DL ^D _S VHLF ^I K SEK LE ^Q K SVHLF _S ^I EK E ^Q K SVHLF SLKKKL Y L _G ^Y DL _S ^D LKKKL Y ^Y L L _S ^D LKKKL P _Q ^E FAEDHNRKDNP ^E L QFAEDHNRKDN P _Q ^E FAEDHNRKDN P _Q ^E FAEDHNRKDN P ^E L _G D QFAEDHNRKDN ⁰ KLE FH ^S DIKAIKLE H DIKDI KLE FH ₀ NTA _G ^Y NY _G IRDRINTA ^Y F GNY _G ^S IRDRI NTA _G ^Y NY ^S DIKAI KLE FH KAI KLE H DIKAI GIRDRI NTA _G ^Y NY ^S DI GIRDRI NTA ^Y F GNY _G ^S IRDRI O M A F D W T A D R W I N M A F D W T A D R W I N M A F D W T A D R W I N M A F D W T A D R W I N M A F D W T A D R W I N ₆ ^W

0 ^{5 0} _{1 7} ^{. .} _{7 5} ⁷ 6 _{7 8 9 0} ⁹ ₉ 0 ^{0 0 1} ₁ ⁸

1 _{8 3 3 3 3 B 7} ⁴

I TEDVVKPY I ETEDVVKPY I DVVKPY KPY I ETEDVVKPY L ^H E G IAIL _G ^L L _G ^H KVIAIL ^L I G L ^H ETEDVV G KVIAIL _G ^L L _G ^H NKVIAIL _G ^L NR _G ^{D R} NKV QYY EVLFTNR ^D NKVIAIL _G ^L L ^H ETE G _{G Q} ^R YY FT NR _G ^{D R} N QYY EVLFT NR _G ^{D R} N QYY VLFT NR _G ^D _Q ^R YY VLFT KFIKVN _Q ^I IKVN ^I EVL Q VKKI KFIKVN _Q ^I KKI KFIKVN ^I E Q VKKI KFIKVN ^I D Q VKKI KK RTEE ^L VKKIKF SA M EE ^L V SA K RTEE _S ^L A M KK TEE _S ^I A M II _G ^Q LFLPPN _S ^{D S} KK ^Q RTEE _S ^L A M GLFLPPN _S ^{D S} KK RT LPPN ^D M S ^S K I _G ^Q LFLPPN _S ^{D S} II ^Q R GLFLPPN _S ^{D S} YILFKREVL ^F _Q II QHYILFKREVL ^F _Q II _G ^Q LF QH YILFKREVL ^F _Q I ILFKREVL ^F _Q EHLDEK DY _G ^N TIEHLDEK TI EHLDEK DY ^N _Q H Y GTI EHLDEK DY ^N _Q H YILFKREVL ^Y _{Q Q} H Y _G YK _G NEYK ^Y DY ^N G AHPL KANEYK ^Y _G TI EHLDEK Y _S ^N TI KANE _G HPL KANEYK _G ^Y HPL KANEYK ^Y D G AHPL DLENIIM ^D AHPLKA SDAL ENIIM _S ^D DAL DLENIIM ^D A SDAL LENIIM ^D A SDAL DLENIIM _S ^D DAL TALK MV ^T DL KHLA _S TALK V ^K HLA _S ^T TALK MV LA ^T D S TALK MV LA ^{T L} _S TALK NIDI _S EK _G A N DI ^L M SEK _G A LN DI _S ^L EK ^K H GA IDI _S ^L EK ^K H GA ^L MV HLA _S ^T GYEKHRVRH ^I L SEL ^N I GYEKHRVRH _S ^I EL ^N I GYEKHRVRH ^I LN SEL _G ^N YEKHRVRH ^I LN _S EK _G ^K A LD SEL ^N LDI GYEKHRVRH _S ^I EL LIDEKDLNHE VLIDEKDLNHE DLNHE IDEKDLNHE VL LPEEKY ^N EVL ^N VLIDEK EEKY ^N VL L SFLFDAN ^K _{G S} KRR ^Y LPEEKY _G E VL SFLFDAN _S ^{K Y} LP DAN ^K _G E V S KR ^Y LPEEKY ^N VLVDEKDLNHE RR ^Y R _S FLFDAN ^K _G E VL PEEKY ^N V GE S KRR ^Y L SFLFDAN _S ^K MLDNVLV F _Q ^K DNVLV NF ^K KRR _S FLF Q MLDNVLV F _Q ^K LDNVLV F _Q ^K KDK ^S N SV ^T ML SKDK KTI _S ^S V L _S ^T KDK KTI ^S N SV ^T M DK TI ^S N SV ^T MLDYVLV ^S NF ^K K Q KAA ^E KTI SELKVE ^G L G TKAA _S ^E ELKVE _G ^{G E} V L _S ^T ELKVE ^G L _S K G AA ^E K SELKVE ^G L _S KDK KTI _{S G} AK DE LR ^E YAK ^E T KAA _S T ^T LLR ^E T K AK DE ^E T KAA _S ^E EIKVE _G ^G PE _Q ^{F T} L VI ^T _{G Q} RPE ^F DE LLR _G Y AK Q _Q ^F DE Y AK E _G Y P _Q ^{T T} _G Y QRKI _S ^A KVKL ^E _Q LV ^S VI QRKI ^A RPE _Q P _Q ^S _Q RPE _Q ^{F T} LLR Q VI ^T _{G Q} RPE ^F D Q P ^T LLR ^E T Q I _Q ^T VKL ^E P _{Q Q} LV ^S _S KVKL ^E VI QLV _Q RKI _S ^A KVKL ^E P QLV _Q ^S RKI _S ^A KVKL _Q ^E LV ^S V QRKV ^A R SK KKPKYILNYEARKKPKYILNYEARKKPKYILNYEARKKPKYILNYEARKKPKYILNYEAR YDTTFD D TFD LD YDTTFD DAKLDE _G ^{I F} TLDYDT LDE ^I D G ^F T GKLVDAKLDE ^I D TLD YDTTFD D TLD YDTTLD G _G ^F KLI DAKLDE _G ^{I F} KLVDAKLDE ^I D G ^F TLD GKL DLDLNLK ^I _G KLVDAK SFKRIDLDLNLK _S ^I FKRI DLDLNLK _S ^I FKRI DLDLNLK ^I _{G S} FKRI DLDLNLK _S ^I FKR _S ^V TEE DEVRKTEE KDEVRKTEE VRKTEE N KDEVRK IKL ^K N ST ^I K SIDKI DIKL ^K N KDEVRKTEE N ST _S ^I IDKI IDKI KL ^K N ST ^I KDE R _S IDKI D IKL _S ^K T _S ^I IDKI IRNLMEAKRN _G F RNLMEAKRN ^R D IKL _S ^K T _S ^I GF NLMEAKRN ^R D I GF RNLMEAKRN _G ^R F RNLMEAKRN ^R D GF SLFYRNPIF F _S ^I LFYRNPIF NF ^I R SLFYRNPIF ^N NF _S ^I LFYRNPIF ^N NF _S ^I LFYRNPIF WHYKHD F ^N N KHD ^N EK YKHD GYKYIP _G ^{S N} _Q EK HY ^S F EK HYKHD F _Q EK HHKHD ^V NF A _S PLF _G ^W YKYIP ^S F G ^N _Q LF ^W H GYKYIP _G ^N _{Q S} PLF _G ^W YKYIP _G ^{S N} PLF _G ^W YKYIP ^S F G ^N _Q EK SPLF VIKFFNA _Q V A IKFFNA ^A _S P QV EA KFFNA _Q ^A V EA IKFFNA ^A _{S Q} V S FAADLPL ^Y E SFA _S ^V AADLPL _S ^Y FA ^V I S FAADLPL _S ^Y FA _S ^{V Y} EA ^V IKFFNA _Q ^A V EA T TFAADLPL _S ^Y FA N _S D PN ^T F ^T FAADLPL _S FA _S EEL Q F ^E I L G ^L _S D EL I I _S ^N V _S ^E _Q F _G ^E I ^N L SV ^L P N _S ^T D S ^E EL ^E I _S D L GI ^N L SV ^L P N ^{N A} _S ^T F ^E E ^E I L P NPD L V TF _G I _S V _S ^L F ^E E Q F _G ^E I ^N L SV ^L P S _G K _Q ^A N _S DVHKKY ^{A T} F G _G K _Q ^A N _S ^A DVHKKY _G ^{A T} F GK ^A _{Q Q} N ^A F SDVHKKY _G ^A _G K ^A _Q F QN _S ^A DVHKKY _G ^A _G ^T K _Q ^A N _S ^A DVHKKY _G ^A IE KKVDLRK TKKVDLRK IE VDLRK IE RK E TKKVDLRK DH ^N T G EDEITVP ^L IE SDH _G ^{N K} EDEITVP _S ^L DH ^N TKK G EDEITVP _S ^L DH ^N TKKVDL G DEITVP ^L I S DH _G ^N DEITVP _S ^{L L} YV _G ^K KLKDVTLT YV _G KLKDVTLT V _G ^K KLKDVTLT V ^K E GKLKDVTLT YV ^K E GKLKDVTLT GDIEDILYIAIF _G ^L DIEDILYIAIF ^L Y GDIEDILYIAIF ^L Y GDIEDILYIAIF _G ^L DIEDILYIAIF IKLIVKN IVKN N SEK LE ^Q KFIT KL SVHLF _S ^I EK ^Q KFIT LIVK LE ^Q KFIT LIVKN FIT KLIVKN FIT LE _S VHLF ^I K SEK Y L _G ^Y DL _S ^D LKKKLY ^Y _G DL _S ^D LKKKL Y L _G ^Y DL ^D _S VHLF ^I K SEK LE ^Q K SVHLF _S ^I EK K ^Q K SVHLF SLKKKL Y L _G ^Y DL _S ^D LKKKL Y ^Y L L _S ^D LKKKL P _Q ^E FAEDHNRKDNP ^E L QFAEDHNRKDN P _Q ^E FAEDHNRKDN P _Q ^E FAEDHNRKDN P ^E L _G D QFAED NRKDN ⁰ KLE FH DIKAIKLE DIKAI KLE FH KAI KME H ^H _S DIKTI ₀ NTA _G ^Y NY _G ^S IRDRINTA ^Y FH GNY _G ^S IRDRI NTA _G ^Y NY ^S DIKAI KLE FH GIRDRI NTA _G ^Y NY ^S DI GIRDRI NTA ^Y F GNY IPDRI O M A F D W T A D R W I N M A F D W T A D R W I N M A F D W T A D R W I N M A F D W T A D R W I N M A F D W T _S ^G D K W I N ₆ ^W

0 ^{5 0} _{1 7} ^{. .} _{7 5} ⁷ 1 _{2 3 4 5} ⁹ ₉ 1 ^{1 1 1} ₁ ⁸

1 _{8 3 3 3 3 B 7} ⁴

I TEDVVKPY I ETETAVKPY I TAVKPY KPY I ETETAVKPY L ^H E G IAIL _G ^L L _G ^H FMIAIL ^L I G L ^H ETETAV G FMIAIL _G ^L L _G ^H NFMIAIL _G ^L NR _G ^{D R} NKV QYY DVLFTNR ^D NFMIAIL _G ^L L ^H ETE G _{G Q} ^R YFEEVLFT NR _G ^{D R} N QYFEEVLFT NR _G ^{D R} N QYFEEVLFT NR _G ^D _Q ^R YFEEVLFT KFIKVN _Q ^I IKVDV VKKI KFIKVDV KKI KFIKVDV VKKI KFIKVDV VKKI KK RTEE ^I VKKIKF SA M KV ^L V SA K RTKV _S ^L A M KK TKV _S ^V A M II _G ^Q LFLPPN _S ^{D S} KK ^Q RTKV _S ^V A M GLFY N _S ^{D S} KK RT Y PN ^D M S ^S K I _G ^Q LFY PN _S ^{D S} II ^Q R GLFY N _S ^{D S} YILFKREVL ^Y _Q II QHYILFKI ^I P QVL ^F _Q II _G ^Q LF QH YILFKI _Q ^I VL ^Y _Q I ILFKI _Q ^I VL ^Y _Q EHLDEK DY _S ^N TIEHLDEDEDY _G ^N TI EHLDEDEDY ^N _Q H Y GTI EHLDEDEDY ^N _Q H YILFKI ^I P QVL ^F _Q N _Q H GTI EHLDEDEDY _G TI KANEYK _G ^Y NEYLP AHPL KANEYLP HPL KANEYLP HPL KANEYLP AHPL DLENIIM ^D AHPLKA SDAL ENIRE _S ^D DAL ^T DLENIRE ^D A SDAL LENIRE ^D A SDAL DLENIRE _S ^D DAL TALK ^L MV ^T DL KHLA _S TALK A _S TALK K LA ^T D S TALK K LA _S ^T TALK NLDI _S EK _G A D DI ^L K SR ^Y HL G _G ^K A LN DI _S ^L R _G ^{Y K} H GA LDI _S ^L R _G ^{Y K} H GA ^L K HLA _S ^T GYEKHRVRH ^I L SEL ^N L GYEKHIMRH _S ^I EL ^N L GYEKHIMRH ^I LN SEL _G ^N YEKHIMRH ^I LN _S R _G ^Y _G ^K A LN SEL ^N LDI GYEKHIMRH _S ^I EL LVDEKDLNHE VLIDEKMVNHE MVNHE IDEKMVNHE VL LPEEKY ^N EVL ^N VLIDEK EKKY ^N VL L SFLFDAN ^K _{G S} KRR ^Y LPEKKY _G E VL SLLRVAN _S ^{K Y} LP VAN ^K _G E V S KR ^Y LPEKKY ^N VLIDEKMVNHE RR ^Y R _S LLRVAN ^K _G E VL PEKKY ^N V GE S KRR ^Y L SLLRVAN _S ^K MLDYVLV F _Q ^K DYVDL NF ^K KRR _S LLR Q MLDYVDL F _Q ^K LDYVDL F _Q ^K KDK ^S N SV ^T ML SKDKEKEE _S ^S V L _S ^T KDKEKEE ^S N SV ^T M DKEKEE ^S N SV ^T MLDYVDL NF ^K K Q KAA ^E KTI SEIKVE ^G L G TKAA DVE ^G L _S K G AA FDVE ^G L _S KDKEKEE _S ^S V L _S ^T G AK DE LR ^E YAK ^S EFDVE _G ^{G E} T KAA VLR ^E T K K ^S E GELVLR ^E T KAA EFDVE _G ^G ET PE _Q ^{F T} L VI ^T _{G Q} RPE ^F _G ELVLR _G Y AK ^S EF Q ^F _G EL IVI ^T _G Y A Q RPE _Q ^F TIVI ^T _G Y AK ^S ELVLR DY Q RPE ^F _{G Q} PTIVI _Q ^T VKL ^E P _{Q Q} LV _Q ^S RKV _S ^A KVKL ^E PTIVI _Q ^T QLLKRKI ^A RPE _Q PT SKVKL _Q ^E LLKRKV _S ^A KVKL ^E P QLLKRKV _S ^A KVKL _Q ^E LLKRKI ^A R SK KKPKYILNYEARKKPKY LNYEARKKPKY LNYEARKKPKY EARKKPKY LNYEAR YDTTLD ^I D ^F TLDYDTTL _Q ^T LD YDTTL _Q ^T DAKLDE _G LDV ^S D Q ^F T GKLVDAKLDV ^S D TLD YDTTL ^T LNY Q D TLD YDTTL _Q ^T Q _G ^F KLVDAKLDV _Q ^{S F} KLVDAKLDV ^S D Q ^F TLD GKLV DLDLNLK ^I _G KL SFKR ^V DAK SDLDLNIL _S ^I FKRI DLDLNIL _S ^I FKRI DLDLNIL ^I _{G S} FKRI DLDLNIL _S ^I FKRI TEE DEVRKTEE IKL ^K N ST ^I K SIDKI DIKL ^K ND RKTEE ND STE ^I DEV GDKI ^I DEVRKTEE D DEVRKTEE ND EVRK GDKI KL ^K N STE _G ^I DKI D IKL _S ^K TE ^I D GDKI IRNLMEAKRN _G ^R F RNLMLKKRN ^R D IKL _S ^K TE GF NLMLKKRN ^R D I GF RNLMLKKRN _G ^R F RNLMLKKRN ^R D GF SLFYRNPIF F _S ^I LFYRIKIF NF ^I R SLFYRIKIF NF _S ^I LFYRIKIF ^I LFYRI WHHKHD F ^V N KHLIF ^V EK HKHLIF ^V EK HHKHLIF ^V NF _S KIF QEK HHKHLIF ^V NF GYKYIP _G ^{S N} _Q EK HH A _S PLF _G ^W YKYIEA ^N _Q LF ^W H GYKYIEA ^N _{Q S} PLF _G ^W YKYIEA ^N PLF _G ^W YKYIEA ^N _Q EK SPLF VIKFFNA _Q V A IKFFNP ^A _S P QV EA KFFNP _Q ^A V EA ^V IKFFNP ^A _{S Q} V KFFNP _Q ^A V EA STFAADLPL ^Y E SFA _S ^V TFAAD PL _S ^Y FA ^V I STFAAD TFAAD PL ^Y EA I SFA NPD ^S PL _S ^Y FA _{S S} ^V TFAAD L _S ^Y FA EEL ^E V L ^L PNPD ^{S E} ET _G I _G I PD T _G ^S I L P NPD T ^S P GI TF _Q F _G I _S ^N V _{S Q} NAI ^N L SV ^L P NPD ^{N A} _S ^E ET AI ^N L SV ^L P N S F ^E E AI _S V _S ^L F ^E E Q NAI ^N L SV ^L P S _G K _Q ^A N _S DVHKKY ^{A T} F G _G K _Q ^A N _S ^A DLHKKY _G ^{A T} F GK ^A _{Q Q} N ^A N SDLHKKY _G ^{A T} N GK ^A _{Q Q} N _S ^A DLHKKY _G ^A _G ^T K _Q ^A N _S ^A DLHKKY _G ^A IE KKVDLRK TKL ^E DLRK IE RK IE RK E TKL DLRK DH ^N T G EDEITVP ^L IE SDH _G ^{N K} EF _G ITVP _S ^L DH ^N TKL G EF ^E DL GITVP _S ^L DH ^N TKL DL G F _G ^E ITVP ^L I S DH _G ^N F _G ^E ITVP _S ^{L L} YV _G ^K KLKDVTLT YV _G KDVDVTLT V _G ^K KDVDVTLT V ^K E GKDVDVTLT YV ^K E GKDVDVTLT GDIEDILYIAIF _G ^L YIED YIAIF ^L Y GYIED VYIAIF ^L Y GYIED AIF _G ^L YIED IKLIVKN IV ^K V GE E KFIT LIV ^K VYI GE FIT KLIV ^K VYIAIF GE ^Q KFMT SEK LK ^Q KFIT KL SVHLF _S ^I EK ^Q KFMT LIV _G ^K K _S ^Q VHLF ^I K SEK LLK ^Q K SVHLF _S ^I EK LK _S VHLF Y L _G ^Y DL _S ^D LKKKLY ^Y LLK _S VHLF ^I K SEK LL GDILLKKKL Y L _G ^Y DILLKKKL Y L _G ^Y DILLKKKL Y ^Y L ILLKKKL P _Q ^E FAED NRKDNP ^E L QFAEKNNRKDN P _Q ^E FAEKNNRKDN P _Q ^E FAEKNNRKDN P ^E L _G D QFAEKNNRKDN ⁰ KME ^Y FH _S ^H DIKTIKME DDIKTI KME FKDDIKTI KME K DIKDI ₀ NTA _G NY IPDRINTA ^Y FK ^D DIKDI KME FK GNL _S IRDRI NTA _G ^Y NLLIRDRI NTA _G ^Y NLLIRDRI NTA ^Y F GNL _S ^D IRDRI O M A F D W T _S ^G D K W I N M A F D W D H D R W I N M A F D W D H D R W I N M A F D W D H D R W I N M A F D W D H D R W I N ₆ ^W

0 ^{5 0} _{1 7} ^{. .} _{7 5} ⁷ 6 _{7 8 9 0} ⁹ ₉ 1 ^{1 1 2} ₁ ⁸

1 _{8 3 3 3 3 B 7} ⁴

I TETAVKPY I ETETAVKPY I TAVKPY KPY I ETETAVKPY L ^H E G IAIL _G ^L L _G ^H FMIAIL ^L I G L ^H ETETAV G FMIAIL _G ^L L _G ^H NFMIAIL _G ^L NR _G ^{D R} NFM QYFEEVLFTNR ^D NFMIAIL _G ^L L ^H ETE G _{G Q} ^R YFEEVLFT NR _G ^{D R} N QYFEEVLFT NR _G ^{D R} N QYFEEVLFT NR _G ^D _Q ^R YFEEVLFT KFIKVDV IKVDV VKK KFIKVDV KKI KFIKVDV VKKI KFIKVDV VKK KK RTKV ^V VKKIKF SA M KV ^V V SA K RTKV _S ^V A M KK TKV _S ^V A M _S ^I II _G ^Q LFY PN _S ^{D S} KK ^Q RTKV _S ^V A M _S ^I KK RT GLFY N _S ^D Y PN ^D M S ^S K I _G ^Q LFY PN _S ^{D S} II ^Q R GLFY N _S ^D YILFKI _Q ^I VL ^F _Q II QHYILFKI ^I P QVL ^F KII _G ^Q LF QH YILFKI _Q ^I VL ^F _Q I ILFKI _Q ^I VL ^F _Q EHLDEDEDY _G ^N TIEHLDEDEDY _G ^N TI EHLDEDEDY ^N _Q H Y GTI EHLDEDEDY ^N _Q H YILFKI ^I P QVL ^F K N _Q H GTI EHLDEDEDY _G TI KANEYLP NEYLP AHPL KANEYLP HPL KANEYLP HPL KANEYLP AHPL DLENIRE ^D AHPLKA SDAL ENIRE _S ^D DAL DLENIRE ^D A SDAL LENIRE ^D A SDAL DLENIRE _S ^D DAL TALK K ^T DL KHLA _S TALK A _S ^T TALK K LA ^T D S TALK K LA _S ^T TALK NLDI _S ^L R _G ^Y _G A N DI ^L K SR ^Y HL G _G ^K A LN DI _S ^L R _G ^{Y K} H GA LDI _S ^L R _G ^{Y K} H GA ^L K HLA _S ^T GYEKHIMRH ^I L SEL ^N L GYEKHIMRH _S ^I EL ^N L GYEKHIMRH ^I LN SEL _G ^N YEKHIMRH ^I LN _S R _G ^Y _G ^K A LN SEL ^N LDI GYEKHIMRH _S ^I EL LIDEKMVNHE VLIDEKMVNHE MVNHE IDEKMVNHE VL LPEKKY ^N EVL ^N VLIDEK EKKY ^N VL L SLLRVAN ^K _{G S} KRR ^Y LPEKKY _G E VL SLLRVAN _S ^{K Y} LP VAN ^K _G E V S KR ^Y LPEKKY ^N VLIDEKMVNHE RR ^Y R _S LLRVAN ^K _G E VL PEKKY ^N V GE S KRR ^Y L SLLRVAN _S ^K MLDYVDL DYVDL NF ^K KRR _S LLR Q MLDYVDL F _Q ^K LDYVDL F _Q ^K KDKEKEE ^S NF _Q ^K SV ^T ML SKDKEKEE _S ^S V L _S ^T KDKEKEE ^S N SV ^T M DKEKEE ^S N SV ^T MLDYVDL NF ^K K Q EKEE _S ^S V L _S ^T KAA VE ^G L G TKAA DVE ^G L _S K G AA FDVE ^G L _S KDK GET KAA EFDVE _G ^G AK ^S EFD GELVLR ^E YAK ^S EFDVE _G ^{G E} T KAA VLR ^E T K K ^S E GELVLR PE _Q ^F VI ^T _{G Q} RPE ^F _G ELVLR _G Y AK ^S EF Q ^F _G EL IVI ^T _G Y A Q RPE _Q ^F TIVI ^T DY AK ^S ELVLR ^E T GY Q RPE ^F _{G Q} PTIVI _Q ^T VKL ^E PTI QLLKRKI _S ^A KVKL ^E PTIVI _Q ^T QLLKRKI ^A RPE _Q PT SKVKL _Q ^E LLKRKI _S ^A KVKL ^E P QLLKRKI _S ^A KVKL _Q ^E LLKRKI ^A R SK KKPKY NYEARKKPKY LNYEARKKPKY LNYEARKKPKY EARKKPKY LNYEAR YDTTL ^T L Q ^S D ^F TLDYDTTL _Q ^T LD YDTTL _Q ^T DAKLDV _Q LDV ^S D Q ^F T GKLVDAKLDV ^S D TLD YDTTL ^T LNY Q D TLD YDTTL _Q ^T Q _G ^F KLVDAKLDV _Q ^{S F} KLVDAKLDV ^S D Q ^F TLD GKLV DLDLNIL ^I _G KLVDAK SFKRIDLDLNIL _S ^I FKRI DLDLNIL _S ^I FKRI DLDLNIL ^I _{G S} FKRI DLDLNIL _S ^I FKRI TEE DEVRKTEE IKL ^K ND STE _G ^I DKI DIKL ^K ND RKTEE ND STE ^I DEV GDKI ^I DEVRKTEE D DEVRKTEE ND EVRK GDKI KL ^K N STE _G ^I DKI D IKL _S ^K TE ^I D GDKI IRNLMLKKRN _G ^R F RNLMLKKRN ^R D IKL _S ^K TE GF NLMLKKRN ^R D I GF RNLMLKKRN _G ^R F RNLMLKKRN ^R D GF SLFYRIKIF F _S ^I LFYRIKIF NF ^I R SLFYRIKIF NF _S ^I LFYRIKIF WHHKHLIF ^V N KHLIF ^V EK HKHLIF ^V EK HHKHLIF ^V NF _S ^I LFYRIKIF QEK HHKHLIF ^V NF GYKYIEA ^N _Q EK HH A _S PLF _G ^W YKYIEA ^N _Q LF ^W H GYKYIEA ^N _{Q S} PLF _G ^W YKYIEA ^N PLF _G ^W YKYIEA ^N _Q EK SPLF VIKFFNP _Q V A IKFFNP ^A _S P QV EA KFFNP _Q ^A V EA IKFFNP ^A _{S Q} V STFAAD PL ^Y E SFA _S ^V TFAAD PL _S ^Y FA ^V I STFAAD ^Y EA IKFFNP _Q ^A V EA STFAAD PL _S FA ^V TFAAD L _S ^Y FA NPD ^S PL _S ^Y FA ^V _S EET _G ^S I L ^L PNPD ^{S E} ET _G I _G I PD T _G ^S I L P NPD T ^S P GI TF _Q NAI _S ^N V _{S Q} NAI ^N L SV ^L P NPD ^{N A} _S ^E ET AI ^N L SV ^L P N S F ^E E AI _S V _S ^L F ^E E Q NAI ^N L SV ^L P S _G K _Q ^A N _S DLHKKY ^{A T} F G _G K _Q ^A N _S ^A DLHKKY _G ^{A T} F GK ^A _{Q Q} N ^A N SDLHKKY _G ^{A T} N GK ^A _{Q Q} N _S ^A DLLKKY _G ^A _G ^T K _Q ^A N _S ^A DLHKKY _G ^A IE KL DLRK TKL ^E DLRK IE RK IE RK E TKL DLRK DH ^N T G EF _G ^E ITVP ^L IE SDH _G ^{N K} EF _G ITVP _S ^L DH ^N TKL G EF ^E DL GITVP _S ^L DH ^N TKL DL G F _G ^E ITVP ^L I S DH _G ^N F _G ^E ITVP _S ^{L L} YV _G ^K KDVDVTLT YV _G KDVDVTLT V _G ^K KDVDVTLT V ^K E GKDVDVTLT YV ^K E GKDVDVTLT GYIED YIAIF _G ^L YIED YIAIF ^L Y GYIED VYIAIF ^L Y GYIED AIF _G ^L YIED IKLIV ^K V GE IV ^K V GE E KFMT LIV ^K VYI GE FMT KLIV ^K VYIAIF GE KFMT SEK LLK ^Q KFMT KL SVHLF _S ^I EK ^Q KFMT LIV _G ^K K _S ^Q VHLF ^I K SEK LLK ^Q K SVHLF _S ^I EK LK ^Q _S VHLF Y L _G ^Y DILLKKKLY ^Y LLK _S VHLF ^I K SEK LL GDILLKKKL Y L _G ^Y DILLKKKL Y L _G ^Y DILLKKKL Y ^Y L ILLKKKL P _Q ^E FAEKNNRKDNP ^E L QFAEKNNRKDN P _Q ^E FAEKNNRKDN P _Q ^E FAEKNNRKDN P ^E L _G D QFAEKNNRKDN ⁰ KME FK ^D DIKDIKME K DIKDI KME FK ₀ NTA _G ^Y NL _S IRDRINTA ^Y F GNL _S ^D IRDRI NTA _G ^Y NL ^D DIKDI KME FK KDI KME K DIKDI SIRDRI NTA _G ^Y NL ^D DI SIRDRI NTA ^Y F GNL _S ^D IRDRI O M A F D W D H D R W I N M A F D W D H D R W I N M A F D W D H D R W I N M A F D W D H D R W I N M A F D W D H D R W I N ₆ ^W

0 ^{5 0} _{1 7} ^{. .} _{7 5} ⁷ 1 _{2 3 4 5} ⁹ ₉ 2 ^{2 2 2} ₁ ⁸

1 _{8 3 3 3 3 B 7} ⁴

I TEDVVKPY I ETEDVVKPY I DVVKPY KPY I ETEDVVKPY L ^H E G IAIL _G ^L L _G ^H KVIAIL ^L I G L ^H ETEDVV G KVIAIL _G ^L L _G ^H NKVIAIL _G ^L NR _G ^{D R} NKV QYY EVLFTNR ^D NKVIAIL _G ^L L ^H ETE G _{G Q} ^R YY FT NR _G ^{D R} N QYY EVLFT NR _G ^{D R} N QYY VLFT NR _G ^D _Q ^R YY VLFT KFIKVN _Q ^I IKVN ^I EVL Q VKKI KFIKVN _Q ^I KKI KFIKVN ^I E Q VKKI KFIKVN ^I E Q VKKI KK RTEE ^L VKKIKF SA M EE ^L V SA K RTEE _S ^L A M KK TEE _S ^L A M II _G ^Q LFLPPN _S ^{D S} KK ^Q RTEE _S ^L A M GLFLPPN _S ^{D S} KK RT LPPN ^D M S ^S K I _G ^Q LFLPPN _S ^{D S} II ^Q R GLFLPPN _S ^{D S} YILFKREVL ^F _Q II QHYILFKREVL ^F _Q II _G ^Q LF QH YILFKREVL ^F _Q I ILFKREVL ^F _Q EHLDEK DY _G ^N TIEHLDEK TI EHLDEK DY ^N _Q H Y GTI EHLDEK DY ^N _Q H YILFKREVL ^F _{Q Q} H Y _G YK _G NEYK ^Y DY ^N G AHPL KANEYK ^Y _G TI EHLDEK Y _G ^N TI KANE _G HPL KANEYK _G ^Y HPL KANEYK ^Y D G AHPL DLENIIM ^D AHPLKA SDAL ENIIM _S ^D DAL DLENIIM ^D A SDAL LENIIM ^D A SDAL DLENIIM _S ^D DAL TALK MV ^T DL KHLA _S TALK V ^K HLA _S ^T TALK MV LA ^T D S TALK MV LA ^{T L} _S TALK NIDI _S EK _G A N DI ^L M SEK _G A LN DI _S ^L EK ^K H GA LDI _S ^L EK ^K H GA ^L MV HLA _S ^T GYEKHRVRH ^I L SEL ^N I GYEKHRVRH _S ^I EL ^N L GYEKHRVRH ^I LN SEL _G ^N YEKHRVRH ^I LN _S EK _G ^K A LN SEL ^N IDI GYEKHRVRH _S ^I EL LIDEKDLNHE VLIDEKDLNHE DLNHE FDEKDLNHE VL LPEEKY ^N EVL ^N VLFDEK EEKY ^N VL L SFLFDAN ^K _{G S} KRR ^Y LPEEKY _G E VL SFLFDAN _S ^{K Y} LP DAN ^K _G E V S KR ^Y LPEEKY ^N VLIDEKDLNHE RR ^Y R _S FLFDAN ^K _G E VL PEEKY ^N V GE S KRR ^Y L SFLFDAN _S ^K MLDNVLV F _Q ^K DNVLV NF ^K KRR _S FLF Q MLDYVLV F _Q ^K LDYVLV F _Q ^K KDK ^S N SV ^T ML SKDK KTI _S ^S V L _S ^T KDKEKTI ^S N SV ^T M DKEKTI ^S N SV ^T MLDNVLV NF ^K K Q K KTI _S ^S V L _S ^T KAA ^E KTI SELKVE ^G L G TKAA _S ^E ELKVE _G ^G KVE ^G L _S K G AA LKVE ^G L _S KD G _S ELKVE _G ^G AK DE LR ^E YAK ^E T KAA PE _Q ^{F T} L VI ^T _{G Q} RPE ^F DE LLR ^T _G Y AK ^S EL LLR ^E T K ^E T KAA ^E Q _Q ^F _G E ^{T T} _G Y AK ^S E GE Y AK E _G Y P _Q ^T QRKI _S ^A KVKL ^E _Q LV ^S VI QRKI ^A RPE _Q P _Q ^S _Q RPE _Q ^{F T} LLR Q VI ^T _{G Q} RPE ^F D Q P ^T LLR ^E T Q I _Q ^T VKL ^E P _{Q Q} LV ^S _S KVKL ^E VI QLV _Q RKI _S ^A KVKL ^E P QLV _Q ^S RKI _S ^A KVKL _Q ^E LV ^S V QRKI ^A R SK KKPKYILNYEARKKPKYILNYEARKKPKYILNYEARKKPKYILNYEARKKPKYILNYEAR YDTTFD D TFD LD YDTTLD DAKLDE _G ^{I F} TLDYDT LDE ^I D G ^F T GKLVDAKLDE ^I D TLD YDTTLD D TLD YDTTFD G _G ^F KLVDAKLDE _G ^{I F} KLVDAKLDE ^I D G ^F TLD GKLV DLDLNLK ^I _G KLVDAK SFKRIDLDLNLK _S ^I FKRI DLDLNLK _S ^I FKRI DLDLNLK ^I _{G S} FKRI DLDLNLK _S ^I FKRI TEE DEVRKTEE KDEVRKTEE VRKTEE N KDEVRK IKL ^K N ST ^I K SIDKI DIKL ^K N KDEVRKTEE N ST _S ^I IDKI IDKI KL ^K N ST ^I KDE R _S IDKI D IKL _S ^K T _S ^I IDKI IRNLMEAKRN _G F RNLMEAKRN ^R D IKL _S ^K T _S ^I GF NLMEAKRN ^R D I GF RNLMEAKRN _G ^R F RNLMEAKRN ^R D GF SLFYRNPIF F _S ^I LFYRNPIF NF ^I R SLFYRNPIF ^V NF _S ^I LFYRNPIF ^V NF _S ^I LFYRNPIF WHYKHD F ^N N KHD ^N EK HKHD GYKYIP _G ^{S N} _Q EK HY ^S F EK HHKHD F _Q EK HYKHD ^N NF A _S PLF _G ^W YKYIP ^S F G ^N _Q LF ^W H GYKYIP _G ^N _{Q S} PLF _G ^W YKYIP _G ^{S N} PLF _G ^W YKYIP ^S F G ^N _Q EK LF VIKFFNA _Q V A IKFFNA ^A _S P QV EA KFFNA _Q ^A V EA IKFFNA ^A _{S Q} V KFFNA ^A _S P QV EA S FAADLPL ^Y E SFA _S ^V AADLPL _S ^Y FA ^V I STFAADLPL _S ^Y FA _S ^V TFAADLPL ^Y EA I SFA _S ^V DLPL _S ^Y FA N _S ^T D ^E EL I L PN ^T F SD ^E EL I PD F _Q F _G ^E I _S ^N V _S ^L _Q F _G ^E I ^N L N I PD L SV ^L P S ^G EL G ^E I ^N L SV ^L P N ^{N A} _S ^T F ^G E ^E I L P N ^T FAA SD L I T _G I _S V _S ^L F ^E E Q F _G ^E I ^N L SV ^L P S _G K _Q ^A N _S DVHKKY ^{A T} F G _G K _Q ^A N _S ^A DVHKKY _G ^{A T} F GK ^A _{Q Q} N ^A F SDVHKKY _G ^A _G K ^A _Q F QN _S ^A DVHKKY _G ^A _G ^T K _Q ^A N _S ^A DVHKKY _G ^A IE KKVDLRK TKKVDLRK IE VDLRK IE RK E TKKVDLRK DH ^N T G EDEITVP ^L IE SDH _G ^{N K} EDEITVP _S ^L DH ^N TAK G EDEITVP _S ^L DH ^N TAKVDL G DEITVP ^L I S DH _G ^N DEITVP _S ^{L L} YV _G ^K KLKDVTLT YV _G KLKDVTLT V _G ^K KLKDVTLT V ^K E GKLKDVTLT YV ^K E GKLKDVTLT GDIEDILYIAIF _G ^L DIEDILYIAIF ^L Y GDIEDILYIAIF ^L Y GDIEDILYIAIF _G ^L DIEDILYIAIF IKLIVKN IVKN N SEK LE ^Q KFIT KL SVHLF _S ^I EK ^Q KFIT LIVK LK ^Q KFMT LIVKN FMT KLIVKN FIT LE _S VHLF ^I K SEK Y L _G ^Y DL _S ^D LKKKLY ^Y _G DL _S ^D LKKKL Y L _G ^Y EL ^D _S VHLF ^I K SEK LK ^Q K SVHLF _S ^I EK E ^Q K SVHLF SLKKKL Y L _G ^Y EL _S ^D LKKKL Y ^Y L L _S ^D LKKKL P _Q ^E FAEDHNRKDNP ^E L QFAEDHNRKDN P _Q ^E FAEDHNRKDN P _Q ^E FAEDHNRKDN P ^E L _G D QFAEDHNRKDN ⁰ KLE FH ^S DIKAIKLE H DIKAI KME FH ₀ NTA _G ^Y NY _G IRDRINTA ^Y F GNY _G ^S IRDRI NTA _G ^Y NY ^S DIKDI KME FH KDI KLE H DIKAI GIRDRI NTA _G ^Y NY ^S DI GIRDRI NTA ^Y F GNY _G ^S IRDRI O M A F D W T A D R W I N M A F D W T A D R W I N M A F D W T A D R W I N M A F D W T A D R W I N M A F D W T A D R W I N ₆ ^W

0 ^{5 0} _{1 7} ^{. .} _{7 5} ⁷ 6 _{7 8 9 0} ⁹ ₉ 2 ^{2 2 3} ₁ ⁸

1 _{8 3 3 3 3 B 7} ⁴

I TEDVVKPY I ETEDVVKPY I DVVKPY KPY I ETEDVVKPY L ^H E G IAIL _G ^L L _G ^H KVIAIL ^L I G L ^H ETEDVV G KVIAIL _G ^L L _G ^H NKVIAIL _G ^L NR _G ^{D R} NKV QYY DVLFTNR ^D NKVIAIL _G ^L L ^H ETE G _{G Q} ^R YY FT NR _G ^{D R} N QYY DVLFT NR _G ^{D R} N QYY VLFT NR _G ^D _Q ^R YY VLFT KFIKVN _Q ^V IKVN ^V DVL Q VKKI KFIKVN _Q ^V KKI KFIKVN ^V D Q VKKI KFIKVN ^V D Q VKKI KK RTEE ^I VKKIKF SA M EE ^I V SA K RTEE _S ^I A M KK TEE _S ^I A M II _G ^Q LFLPPN _S ^{D S} KK ^Q RTEE _S ^I A M GLFLPPN _S ^{D S} KK RT LPPN ^D M S ^S K I _G ^Q LFLPPN _S ^{D S} II ^Q R GLFLPPN _S ^{D F} YILFKREVL ^Y _Q II QHYILFKREVL ^Y _Q II _G ^Q LF QH YILFKREVL ^Y _Q I ILFKREVL ^Y _Q EHLDEK NY _G ^N TIEHLDEK TI EHLDEK NY ^N _Q H Y GTI EHLDEK NY ^N _Q H YILFKREVL ^Y _{Q Q} H Y _G YK _G NEYK ^Y NY ^N G AHPL KANEYK ^Y _G TI EHLDEK Y _G ^N TI KANE _G HPL KANEYK _G ^Y HPL KANEYK ^Y N G AHPL DLENIIM ^D AHPLKA SDAL ENIIM _S ^D DAL DLENIIM ^D A SDAL LENIIM ^D A SDAL DLENIIM _S ^D DAL TALK MV ^T DL KHLA _S TALK V ^K HLA _S ^T TALK MV LA ^T D S TALK MV LA ^{T L} _S TALK NLDI _S EK _G A N DI ^L M SEK _G A LN DI _S ^L EK ^K H GA LDI _S ^L EK ^K H GA ^L MV HLA _S ^T GYEKHRVRH ^I L SEL ^N L GYEKHRVRH _S ^I EL ^N L GYEKHRVRH ^I LN SEL _G ^N YEKHRVRH ^I LN _S EK _G ^K A LN SEL ^N LDI GYEKHRVRH _S ^I EL LVDEKDLNHE VLVDEKDLNHE DLNHE VDEKDLNHE VL LPEEKY ^N EVL ^N VLVDEK EEKY ^N VL L SFLFDAD ^K _{G S} KRR ^Y LPEEKY _G E VL SFLFDAD _S ^{K Y} LP DAD ^K _G E V S KR ^Y LPEEKY ^N VLVDEKDLNHE RR ^Y R _S FLFDAD ^K _G E VL PEEKY ^N V GE S KRR ^Y L SFLFDAD _S ^K MLDYVLV DYVLV NF ^K KRR _S FLF Q MLDYVLV F _Q ^K LDYVLV F _Q ^K KNKEKTI ^S NF _Q ^K SV ^T ML SKDKEKTI _S ^S V L _S ^T KDKEKTI ^S N SV ^T M DKEKTI ^S N SV ^T MLDYVLV NF ^K K Q EKTI _S ^S V L _S ^T KAA VE ^G L G TKAA KVE ^G L _S K G AA LKVE ^G L _S KNK G AK ^S ELK GE LR ^E YAK ^S ELKVE _G ^{G E} T KAA T ^T LLR ^E T K ^E T KAA ELKVE _G ^G PE _Q ^{F T} L VI ^T _{G Q} RPE ^F _G E LLR _G Y AK ^S EL Q ^F _G E ^T _G Y AK ^S E GY AK ^S E _G Y P ^T _G E Q _{Q Q} RKI _S ^A KVKL ^E _Q LV ^S VI QRKI ^A RPE _Q P _Q ^S _Q RPE _Q ^{F T} LLR Q VI ^T _Q RPE ^F _{G Q} P ^T LLR ^E T Q I _Q ^T VKL ^E P _{Q Q} LV ^S _S KVKL ^E VI QLV _Q RKI _S ^A KVKL ^E P QLV _Q ^S RKI _S ^A KVKL _Q ^E LV ^S V QRKI ^A R SK KKPKYILNYEARKKPKYILNYEARKKPKYILNYEARKKPKYILNYEARKKPKYILNYEAR YDTTLD D TLD LD YDTTLD DAKLDE _G ^{I F} TLDYDT LDE ^I D G ^F T GKLVDAKLDE ^I D TLD YDTTLD D TLD YDTTLD G _G ^F KLVDAKLDE _G ^{I F} KLVDAKLDE ^I D G ^F TLD GKLV DLDLNLK ^I _G KLVDAK SFKRIDLDLNLK _S ^I FKRI DLDLNLK _S ^I FKRI DLDLNLK ^I _{G S} FKRI DLDLNLK _S ^I FKRI TEE DEVRKTEE KDEVRKTEE VRKTEE N KDEVRK VKL ^K N ST ^I K SIDKI DVKL ^K N KDEVRKTEE N ST _S ^I IDKI IDKI KL ^K N ST ^I KDE R _S IDKI D VKL _S ^K T _S ^I IDKI VRNLMEAKRN _G F RNLMEAKRN ^R D VKL _S ^K T _S ^I GF NLMEAKRN ^R D V GF RNLMEAKRN _G ^R F RNLMEAKRN ^R D GF SLFYRNPIF F _S ^V LFYRNPIF NF ^V R SLFYRNPIF ^V NF _S ^V LFYRNPIF ^V NF _S ^V LFYRNPIF YHHKHD F ^V N KHD ^V EK HKHD GYKYIP _G ^{S N} _Q EK HH ^S F EK HHKHD F _Q EK HHKHD ^V NF A _S PLF _G ^Y YKYIP ^S F G ^N _Q LF ^Y H GYKYIP _G ^N _{Q S} PLF _G ^Y YKYIP _G ^{S N} PLF _G ^Y YKYIP ^S F G ^N _Q EK SPLF VIKFFNA _Q V A IKFFNA ^A _S P QV EA KFFNA _Q ^A V EA IKFFNA ^A _{S Q} V STFAADLPL ^Y E SFA _S ^V TFAADLPL _S ^Y FA ^V I STFAADLPL _S ^Y FA _S ^V TFAADLPL ^Y EA ^V IKFFNA _Q ^A V EA SFA _S TFAADLPL _S ^Y FA NPD ^G EL V L PNPD GI _S ^N V _S ^{L G} EL ^E V PD F _Q ^A F ^E _Q F _G I ^N L SV ^L P N S ^G EL ^E V PD L GI ^N L SV ^L P N S ^{N T} F ^G E ^E V L P NPD L V T _G I _S V _S ^L F ^G E Q F _G ^E I ^N L SV ^L P S _G K _Q ^A N _S DVHKKY ^{A T} F G _G K _Q ^A N _S ^A DVHKKY _G ^{A T} F GK ^A _{Q Q} N ^A F SDVHKKY _G ^A _G K ^A _Q F QN _S ^A DVHKKY _G ^A _G ^T K _Q ^A N _S ^A DVHKKY _G ^A IE AKVDLRK TAKVDLRK IE VDLRK IE RK E TAKVDLRK DH ^N T G EDEITVP ^L IE SDH _G ^{N K} EDEITVP _S ^L DH ^N TAK G EDEITVP _S ^L DH ^N TAKVDL G DEITVP ^L I S DH _G ^N DEITVP _S ^{L L} YV _G ^K KLKDVTLT YV _G KLKDVTLT V _G ^K KLKDVTLT V ^K E GKLKDVTLT YV ^K E GKLKDVTLT GDIEDILYIAIF _G ^L DIEDILYIAIF ^L Y GDIEDILYIAIF ^L Y GDIEDILYIAIF _G ^L DIEDILYIAIF IKLIVKN IVKN N SEK LK ^Q KFMT KL SVHLF _S ^I EK ^Q KFMT LIVK LK ^Q KFMT LIVKN FMT KLIVKN FMT LK _S VHLF ^I K SEK Y L _G ^Y EL _S ^D LKKKLY ^Y _G EL _S ^D LKKKL Y L _G ^Y EL ^D _S VHLF ^I K SEK LK ^Q K SVHLF _S ^I EK K ^Q K SVHLF SLKKKL Y L _G ^Y EL _S ^D LKKKL Y ^Y L L _S ^D LKKKL P _Q ^E FAEDHNRKDNP ^E L QFAEDHNRKDN P _Q ^E FAEDHNRKDN P _Q ^E FAEDHNRKDN P ^E L _G E QFAEDHNRKDN ⁰ KME FH ^S DIKDIKME H DIKDI KME FH ₀ NTA _G ^Y NY _G IRDRINTA ^Y F GNY _G ^S IRDRI NTA _G ^Y NY ^S DIKDI KME FH KDI KME H DIKDI GIRDRI NTA _G ^Y NY ^S DI GIRDRI NTA ^Y F GNY _G ^S IRDRI O M A F D W T A D R W I N M A F D W T A D R W I N M A F D W T A D R W I N M A F D W T A D R W I N M A F D W T A D R W I N ₆ ^W

0 ^{5 0} _{1 7} ^{. .} _{7 5} ⁷ 1 _{2 3 4 5} ⁹ ₉ 3 ^{3 3 3} ₁ ⁸

1 _{8 3 3 3 3 B 7} ⁴

I TEDVVKPY I ETEDVVKPY L _G ^H DTEFM ^H L ^H E G IAIL _G ^L L _G ^{H K} IILH L _G DTEFMKI _G ^N V _G ^L L YFLIEDYK ^S NR _G ^{D R} NKV QYY DVLFTNR ^{D R} NKVIAIL _G ^L NR G _Q YY FT KY _G ^{D R} N QY ^I E _Q ANEI NR AKPT L _G ^H ETE IAK ^N _{S G} P SIVKN L KY _G ^{D R} N QY ^I EK SIVKPLI NR N _S ^D IKK _S ^P KT KFIKVN _Q ^V IKVN ^V DVL Q VKKI KK AVIAD _G ^N T KKIKVDVVALV KF _G ^D _Q ^R YYIRLPHY KK RTEE ^I VKKIKF SA M Y EVF AIT RA V II _G ^Q LFLPPN _S ^{D S} KK ^Q RTEE _S ^I A M ^I KV GLFLPPN _S ^{D S} II _Q RA H _S ^I L _Q ^K N FI _G ^Q LF ^{Y I} E Q _S ^I I _Q ^S KKVKV N LNID SEH II T _Q ^K A _C ^A AA YILFKREVL ^Y _Q II QHYILFKREVL ^Y _Q FIVLF QH HHLFTAE ^L V SA HLFTAE ^L V SAE ^E R EHLDEK NY _G ^N TIEHLDEK TI KALDELPPN ^G L GE ^F R C KALDELPPN ^N I ^S M _G LFLPV ^E R KANEYK _G ^Y NEYK ^Y NY _G ^N G AHPL DLNEY ^K _G L _Q HLFT NV ^T N _G Y GFRR DLENIIM ^D AHPLKA SDAL ENIIM _S ^D DAL TAERL ^R AVLNI LNEY _S KA E _Q ^R I ^L KP Q NY ^S D AERL ^R AVL Q NYF ^K T QADL ^L D GEYR ^H E G V _G NI TALK MV ^T DL KHLA _S TALK V HLA _S ^T LE K _G ^{H Q} _S T G _S ^S V LLE K _G ^{Y N} LDI _S ^L EK _G A N DI ^L M SEK _G ^K A LN ^N L GYDI _S ^L IM ^D P SDVA ^N YDI _S ^L IM ^D A SD ^G LN TAERLIM _S ^I ARNK GEL GYEKHRVRH ^I L SEL ^N L GYEKHRVRH _S ^I EL LIEKHMV ^S _G IEKHMI ^N LLD ^L MVPNP LVDEKDLNHE VLVDEKDLNHE K ^K H GA ^T L _Q L QLY VLDDKEK ^K H GA ^T KI _G YDI _S EKVL _S ^T _G ^V Q LVEKHRVNY _G ^K LL VL LPEEKY ^N KE EVL ^N VVLDD K _G E KRYLPRVRHERRRRYLPRVRHV _S ^A _S ^E VLEDKDL AR RR _S ^Y FLFDAD ^K _G LPEEKY S KRR ^Y _S FLFDAD _S LNHERVMLTFLDLNHEAVKRYLPEE _S ^D DD ^I F SE MLDYVLV DYVLV NF ^K KMFTFLD Q KDDYVEEDYT DDYVEEDYRLT MLTFLFD H AF KNKEKTI ^S NF _Q ^K SV ^T ML SKNKEKTI _S ^S V L _S ^T DKDK _G ^{Q N} K S A DKFDKDKLT KDD VLV _G ^K A _G ^L L KAA VE ^G L G TKAA ^K A ^K DKF V NKN ^K K _S ^K IV KRY KA ^D KTIRHHM _S ^D AK ^S ELK GE LR ^E YAK ^S ELKVE _G ^{G E} T _S K _S L _S ^S IVN ^Q _{S S} PE ^A E VRRAK ^K _G F ^T L _S ELKNH RA PE _Q VI ^T _{G Q} RPE ^F _G E LLR _G Y PE ^A EI Q ^F _G ET KTEIFI V ^F _G ETI ^S N SI I KP ^S E V Y _Q ^T R VKL ^E P _Q ^S P _Q ^T I _Q ^T QLV _Q RKI _S ^A KVKL _Q ^E LV ^S V QRKI ^A RV _Q EPL SKK _S ^K LLLTILRNEE K ^K _Q EPLKTE S ^L FLTILRN _G ^R RV _S ^{Q F} _{G Q} NP _Q ^{T E} DV ^S KKPKYILNYEARKKPKYILNYEARYDP YH YDTTLD D TLD LD DAA _S ^K LV ^S VV D _S H VV I ^F TLDYDT _Q RK ^V F Q ^V Y AA ^K Y SLV _Q ^S RK ^V ND KIL LI ^S _{S Q} NE ^S _{G G Q} EVYDK _Q ^I YIL _S ^S ITD _S ^L DAKLDE _G LDE ^I D G ^F T GKLVDLKLDILNYP ^L _G D SL DLKLDILNYPLD DAALLD EKKT DLDLNLK ^I _G KLVDAK SFKRIDLDLNLK _S ^I FKRI THELYN TEE DEVRKTEE ^I DL YF THELYN DL G ^L R _S ^L KKIKENNE _G ^{I Y} E LDLDE ^I T GLRKLL SF ^K D G TH NIKVVVEE VKL ^K N ST ^I K SIDKI DVKL ^K N KDEVRKIKENNE ST _S ^I IDKI K _S FLPF VRLKTLK ^L K SFL F IK _S ^E _G ^I L KRKIFF VRNLMEAKRN _G ^R F RNLMEAKRN ^R D VRLKTL GF ALDIMIKDEVL ALDIMIKDEV _S ^L F VR KT _Q ^I INYN SLFYRNPIF F _S ^V LFYRNPIF NF FYKAIDKKK _G ^{T W} HFYK KYKAL _Q ^L LMAADF _S ^L _G ^{L Y} HHKHD F ^V N KHD F ^V EK ^W H GYHKNEAKRKIP _G YHKN ^E IDK QAKRKKF HFYRNP K ^{V S N} _Q EK HH _Q YA GYKYIP _G ^A _S PLF _G ^Y YKYIP _G ^{S N} _Q LF KYINPIFII IKYIN IFIPA _G ^W YNKTE ^F FPKN VIKFFNA _Q V A ^V IKFFNA ^A _S P QV EA ^V I STKFF T _G ^A _S ^V TKF K _S ^P F T A ITYIK ^S _{S G} DD P STFAADLPL ^Y E SFA _S TFAADLPL _S ^Y FANPFAD _S ^KS F G ^N L SAN NPFA _S ^F H ^N V _C ^L P _S ^V TKFFNPDK _S ^Y L _S ^K NPD ^G EL V L PNPD ^G EL V P _Q ^A VFP _S ^F D FL PFEKDLKRLEN TF _Q F _G ^E I _S ^N V _S ^L _Q F _G ^E I ^N L SV ^L P D T _S ^T F GN ^E ED LPLDNI ^T F GK ^E EN _S ^{G A} _{S Q} V GK _Q ^A N _S ^A DVHKKY ^A F G _G K _Q ^A N _S ^A DVHKKY _G ^A IK ^A _{Q Q} T ^A D SM ^A _Q ADLPLDI ^A N G FN LDIFVIV IE AKVDLRK TAKVDLRK DH ^E I IL IK _Q T MEI KNL _G ^T E ^D E Q _Q I ^N K SENKDH _S EEAID _Q ^P K _S ^AF HY SV ^Q KI SRK _G ^A DH ^N T G EDEITVP ^L IE SDH ^N T _S ^S FRI ^N G ^{L N} TRF KEDEITVP _{S G} AEVHKKKL _G ^N EVHKKKT DH VKKV _Q ^A VVKL LYV _G ^K KLKDVTLT YV _S KLKDVTLT ^L Y GEV _G ^K KK DLNY ^L Y V ^K A GKK DLNRF Y _G ^L NNPLII GDIEDILYIAIF _G ^L DIEDILYIAIF IDDD _Q ^V ITW ^L _G E IDDD _Q ^V ITWVT _G ^L KL ^G E SKLAI KD _S ^{F I} KLIVKN IVKN K IA ^G _{S C} I ^I K SELIVKTDIANL VFEDIII _S ^N FK SEK ^Y LK ^Q KFMT KL SVHLF _S ^I EK ^Q KFMT ^I K SELIVK V _C ^D IIE YEK IILYIIHL _S ^I ELILKDHKD ^T Y L _G EL _S ^D LKKKLY ^Y LK ^D _S VHLF YEK II GEL _S LKKKL PEL _G ^Y EID K E _S ^F NAL _G ^Y EID P _Q ^E FAEDHNRKDNP ^E L QFAEDHNRKDN KLFAEKN _S ^{S E} L NLFAEKD ^S K S ^{E Y} N YAA RDDL ^Y _{C G G} I AI ^Y I GDLVIT ^T _G I Q E ⁰ KME FH DIKDIKME ^Y FH DIKDI NT T ^V _{G 0} NTA _G ^Y NY _G ^S IRDRINTA _G NY _G ^S IRDRI NA ^{E Y} FL S _G NL ^L _S TY _S ^E NT ^E FLT ^V TK ^K ILADD DIK _G ^K E G NL O M A F D W T A D R W I N M A F D W T A D R W I N M F F D W D ^K _Q RDA ^{Y L} NA _{S G} NL ^L _S DN ^F _{Q S} N H ^D G N D K I _Q M F F D W D ^K _Q R G N I K E N M _G ^N _G ^{N Y} F G N Y I ^Y I Q K W L _S ^N

6 ^W 0 ^{5 0} _{1 7} ^{. .} _{7 5} ⁷ 6 _{7 8 9 0} ⁹ ₉ 3 ^{3 3 4} ₁ ⁸

1 _{8 3 3 3 3 B 7} ⁴

KYDKE _S ^D P ^E F _G ^D _Q ^R YAIKL _S ^D F _G ^L KYAE ^L PVADM DLT KDKFEK _Q ^L KKIKV _Q ^Y _S ^{I N} KKDRFYE ^I M _S D K SIVD KK KVYNNA T KKEE _C ^Y _Q PEVFE L F _Q ^L KLLHTEI II KAAE ^L N L FKF SL ^K _{G S} T LVT IVTL PT RMKDV ^D K GVP KI F _Q ^T _Q ^T _G ^Y VT ^Q F SK ^I I _Q ^I SIALFVPT _G ^T KY ^I ILE ^Y L R D _S ^V REKILAFE GL _G ^VG _G LFLPP GH TEVIVTNKFL ^F FM ^Q YF _Q ^K ARIA S HHLFT VA N H KH _G ^M VY DALA THLFMLNEVPK ^S _Q ID ^L E SK Q KHE _Q ^I HIMPNYM MPIKKK _G H _S ^D IALEL ^L I QI DER IVWNY KAEDKM ^S DRFAKALDE ^R A Q ND ^G L GEL ^S DLLR KD ^D V RAL SV ^G L GN DLNEYR _G ^Q NA I ELYIPR ^I VLKE AL ADLNEYK _G ^H GNYII EP _S ^ME R _G ELL QR _S ^G ILLII TAERLIM ^D H I WLF SA ^T K Q TATD _S ^L KIKAYD TADRLEMPN ^I P SLL AATFLKV APY E NTEETNPE LLE MV ^E MAK NTDIRRINN E IIVLEA L _G ^D DNA F _S ^A _S ^S EKKA T K _G ^N YDI _S ^L EK ^K HV _S ^A _S HL GHEAV Y _S ^F GYLKKME ^K H TLL L _S ^P MKNY ^T LDYVD EKHW KFDM _G ^L Y _Q ^N VLIEKHRVRYTLT _G ^K II LVDDPAE ^G L _Q V QYPY ^G YD QIE ^K L _{S G} ^S YKDNE DEAD ^L FVL S LLYA D VLDDKDLNDKMT HLD VLELLKVNADE ILE ^K H N AV SK ^A V QI ^D A _S E S I VL _C ^AA EF GKVVRHA ^A LK FY ^G IE QIFAKRYLPEEDNKRY RRK KREFVDIKD RR IPDE ^D F ^N I KREDPTINHK ^E _{Q G} L ^R A S PD ^I K GE MLYYKEKT ^M _S ML _S ^Y LLED ^K _{Q G} A ^G _{G G} E MLIILLKAY D Y ^H YFNV ^E AR GKT ^T MLTFLFDKIVRRKPE Q KDDYVIV RDTDEFL ^H _G ^I KVFVRH ^K N KDENYILTD _S ^R N R ^E _{S G} KYIIIKAKN ^S EIRKLDD KAEKEI ^R _G ED KDD SHKP EKLI ^T _Q ^K T DKTI _S RN RLEE RK KLT _Q ^A VHVF ^K A S ^{K N} H _Q LT RAAATK ^S NIA LNKAKLKTTEA _S K _S ^K TV ^G D NKD D _S VL ^{D A} EKLLAME PE ^A ELK GETILK ^V _{S Q} EVYEH IE _S LYPK P ^K _{S Q} ^T ETK _S YVE GELI ^S KKKLDV _Q ^S S VDEMKILVEK ^E RV C NF _{S Q} K V ^F EPH VYPLD H LPL ^D LLR SYI VDIV V ^I DPT ^A DEK QNT Y L KNE LR N R RE _S ^K _Q ^RR KIF QNTL K ^K _{Q S} LFLI _Q ^S R ^K L TNKKTK _G ^I KNLK K ^D _{Q S} LLLW _Q ^S TVK _S ^A RN ^S D SLKTE _G ^I VV _S ^S K R ^T D QAHKL FE YDP N _G ^{L L} E SF ^K E _S E G D YDLIDIKNIKD YDKKYVLTEMAK NDMMLKRK D NLI ^I KK ^I K GVDAA ^K YIL SLN DFL L V ^E A CE DAKTMIKDE LTI ^I LRVLR _Q ^Y VFYKMKNY ^N A GHE _S ^R YII _S ^{G R} _{S G} RRFLI DLKLDE _G ^I V _S ^L F VLK DLYKNDI ^S Y DAA LDE _G VLILD DLVKEDID _S KKYKAHL KHEMTEA ^I R _S RNDLD SV DT IFEKTKNRI TKKYIAA ^L KYL II ^A F THELYLK ^L E MKDVMWPNK ^D N GAEI ^T E QLPNLKNY ^I _Q PLRRV _S ^T _Q N ^W R G ^{Q T} I S _Q ^Q IKENNIKDRKKF KM S NLKRMLLAT _G ^K IF ^E _{Q Q} VVRLKTEIDFVPA _G ^W RK VRDKRV ^S DYKHLVRLKTIID ^V K ^D LEKFFNP G VRFKDL N _Q ^F VTRRFEEKY ALDIMEAK T A LT ALLEED _G TLPYKALEIM ^F _{Q G} ^R N AL ^S DKTMAA A H _S ^{T L} KK GPI _S ^{K W} HDIIAPTKYLY HFYR ^D A QP ^I _G P SF F H ^D _G ^E IP _{G Q} NATRALE T ^Q V QAL _G ^I KTAYLK ^W HFYKNPI _S ^N A _C ^L P _S ^V HV GYHKN FVFL GYFYFYLFFILR _G ^W YNKEN ND ^Y N SEF _G ^W YKT _S ^A DLIF Y R HRR A PA ^A AYN VIVKKEE YIA _G ^S DKMLK I T F ^N H ^F D ^V IKYI _S ^K _G ^S STPYEPA ^S ETET IT QKEVE _S ^V TKFFEAKRVEF _S ^V T _G ^{S K} LE ^Q _S N ^L K _Q Y ^I DE _Q ^T Y _G ^E KL _S TKFFDP ^A LDI _G IF Q KNL _G ^D TK NPKF DVPRKLYNPFEADLIFKF ^K _G IA ^S _S FP _G LDV _Q DLNLY NPFADDLP _S ^N EEAIP QV T RKNHTKEKV ^K T GH TYFD _S ^A DTIFWE RDNF ^A NKI _G F PL ^E L GVI R P KREFKV ^T FD EM KKKT DY _G ^N GK ^E AF ^E I QILNRF KA GT RLDI LL ^{L T} YNE G _G DP ^D R _S YIDD ^E V QI ^{L R} _S YH _S TINT _S ^{Q A} LA P _G ^T ELIVT SFI ^S _S I ^L QV ^S I ^V K SLAWEE Q ^{T K} I ^Y E IK ^A _{Q Q} T TWVT _G DL IN _S ^N _Q ^E EY I _{S Q Q} ^MS D _S A Q ETA DH ^S AVH DHTNKAIDT ^Q P GLIDH AATPM ^T Y QK ^A IEN G DHI ^Y KV GE HKI Y ANL ^V IVMYPHA GKEEAATF ^N T _S K ^V DIANL IYA LY NKHIM ^L T DLE _G ^N I TEFNT KLFD ^L Y _G IIHL NY GEV _G ^KA D _Q I QKKDK N YT ^{A KE} KEI MPL YFAE _G ^G _G ^I _{C G} A ^N T G ^K V TD ^K V Q ^S Y _{G Q G} ^L TL _{G Q} DEI ^{K A} _S DLD _G ^L AR ITT I DL ^A V SVMNLV DDIVYV _G ^E _G ^Y I IKL IVV _G I _G TY _S ^S K _Q ^M F IADDK KKKT IVA ^Y I GN ^K K QDDVK _Q ^K T _G ^{H T} V S FEFIDPVV ^I KI SELIVID NTK KDE TEIDEDD KE I _S ^I E VF ^L H SDLVIF TEFDWLAYIKAAEL _S ^D TN YELIDIE _S ^K LV _G ^N LYD ^L I S VIEITKIT YE KPD ^Q RKYTR ^Y EK IKN _S ^N RDN _S ^F NNK NEM FKILLK TPKV _G ^Y EKNDID F PE _G ^M ERH _S ^{T N} RVEN E _S VL _G ^Y ELT N EN NFY S INL F ^K Y GE ^R F _G KVVYE QVKPVKAL KLFAEL ^L K _S ^K LANDA ^{0 K} LM _G ^Y NA VK _Q ^K LLAELKYIW _S ^S L KI IIY L _Q ^V NAL LE KMFAELVI _{0 Q} ^S FAWL ^T N QNIVF ^S K GR FLI KV ^T N RT _S ^T D T _Q ^V NE E RI _G ^D RF ^N T ^{E Y} FD ^K _{Q G} NKYFL SA _{S G} NHFIDETI ^Q KA SDK O M _G R Y P D A I N I E R M _G ^N _G ^N _G ^Y N D T _S ^Q V I _Q L M A K N _G ^E A E H V _Q ^M _G ^S K M L V L K _S ^T _G ^{Y K} LV S T P _Q ^E M F F D W Y V E K I I E M I N ₆ ^W

0 ^{5 0} _{1 7} ^{. .} _{7 5} ⁷ 1 _{2 3 4 5 6} ⁹ ₉ 4 ⁴ ₃ ⁴ ₃ ⁴ ₃ ⁴ ₁ ⁸ 3 ₃ ¹ ₈

B ₇ ⁴

VYFILTRD FKFVYFILTR _S ^{E S} MDT _S ^T _Q ^K NYTV KIKV YETF KII KYETF D LVAYY LVTD LVALY ^Q _{S G} VELTWIMAPA ^S K QII RT ^K NVLLV QDDY ^S K K ^L I QI _Q ^I LV K P ^T V CTLLIKN RIAP ^T V CTLLIKN EPEETEDRDRTYYM _G ^K LYLP ^I V _Q K DFV K ^D A _S EHIL _G ^{D R} I QMHAKLP ^A K S IL _G ^{D R} I QM DND ^A VYN QKAVY ^S H GH ^D DFV SDND ^A VYNK DADIM QKAVY YEFLR ^I N CV ^Q F SA ^D KIKHIFT LIKYKINV QD ALDE ^R N _S DE Q ^N IK HKL ILPN ^S F KLIKY G HKL IRYWNDPK WLFIRYWNDPK LNNKKKVVHKL ^I K QDLEEYR _G ^{H K} H GA ^K _G LK S TKAEL _Q ^K F ^D K S KAEL _Q ^K KMI M MAKKMI AITTAERVIMRHF _Q ^K AELLFY ^M EVA QEDI ERI ^I DHV G ATA HL ^I DHVM RLEKIELLH G ^I AKA AIFLLVHPLD LLE MVNH A TLRVD ^G L ELLFY GH TA TL IKKR _S ^I HAK ^F ERI SIKKR _S HAK ^V F G N ED I ^N LIEKDHLY ^K Y GIILIEKDHIY ^H F _S ^E N ^I RN QNN ^{E P} _G YDI _S ^L DKKY ^G LNT G L _S ^L DIR _G ^F YT HRVAD ^{E L} YE _Q ^E _S ^L EKKNKN ^N L _S ^L EK _G YE _Q ^E _S ^L KFIIDFTILHLDKFIIDFT ^Y _G TV ^A RDL ^L _{Q S} LI QE KEFAKDN AKD ^I _G R GLYYLI ^A _{Q S} KL N ^L VLEDKDL ^T _{S C G} ^N Q EHVLDNFL TV HVLDN IDDPLND ^E KRRKKEL CYKPEIDEPLN _G ^T DK TP A _S ^L R ^K N _S KRYLPEE ^S N SIT _S ^A K LDIKI ^K L QYVY LDIK GHIMLTFLFDTEEA ^V REKPT _Q ^S DD _S ^V REKP YAY VKLDDYAY K DDYVLVLRVL ^T _{S S} MLEELLW ^N A QDW MLEEL KT ^S LIK G ^S D L LEEKT ^S LIKIY ^K K GVWH ^A D QVKNN G D IKRITDRDKDK _Q ^G Y ^G K SKA DKTIVVKLTKDYLVI N _S ^F KDYLV YK _S ^N A _Q R _S ^D K _S ^K NKDYK _S ^N A _Q ^S R _S ^E R KPDD TPAK _S ^K LKRKKRYRETFKK _G ^{I K} H SAN RETFK FDELPNNTYYEHFDNLPNH ^{K V} H A EVN ^T _{S S} HVNVV ^N KP QIF _S ^{G Q} PE ^S E F _G E ^T VNYVRRKKEPEVKAHK _Q ^E KKEPE DDI ^E VKT QIYD ^Q H LEVN S _G ^M E _S ^K EDDI ^E VKE _C YVMDNKA QIYDN ^M LAEKD ^P FDA S FK ^S _Q V _Q DFIRKME GMK ^H _Q DP SLILI _Q ^S N ^K ETIKVHRY ME VV VHINETD AVV VHINF _G KLALD _G ^D T _Q ^S EDL YDK IL ^I K SF ^G R ^T _S DILHET _Q ^K ET S ^S P GLEAVPII ^{L T} _{S S} ^S P K _G L PI _G EDHPN V _C ^E EPI _G ^E EDHPDT EAFVYPTDT _G ^K DAA ^K Y SLD DD ^V _G P _Q ^L QEIYD _Q ^F VYFPKNLK ^E _{Q G} YD _Q ^F VY TEFA ^V YLL _S ^P VLKTEFA ^V YRL ^S Y QI ^I KNILLRKLLDLDLDE _G ^I DKPFKDVLVTI NIKDADVLVT KNI IEAHL NI EPTH DYWDLK SAK ^Y _Q RV SYET ^Y _Q RVI _S ^P DE _G TWTDI SYET TIPKNH ^M A QA ^E TNIKKR LK ^G P _G ^S DE PNTFTRV ^L A M _S ^K AK QI ^W K GRKPNTFTRL ^L DDR QAVIL TLIDHY ^Q IK _S TLIKIF ^Y E SF ^E D T _G T G _S VRLKTTIF L LL ^K V _{S Q} ^D EP P LT ^G QELKML ^I R SVK _Q ^{H K} V _{S Q} ^D QELK HWFKD K THWFKDFNRI V _G ^D IDVITLNIALKLMEA ^Q V _S ^L FVRAETE EA ^D L GVRAET NPD ^F N A _S ^{F V} L SHVNPD DK P ^A _{S Q} VRYNALEKM ^D NK ILI ^G L _Q F SR NIAYNILI ^G LAFAF ^V D S NY SR FL ^W H GY ^F YRN SKTT HLK ^P _Q DY QIV ^K HMALEKM L _S YR HLK YIW ^H F ^H FNV ^F FF ^Q H GY ^D DL QY ^{T V} D _S ID FYIW ^V D _S VT ^W _{Q G} RKDE V ^G _Q T _S NF ^S PLRKF V ^V ITYIK _G I VPD _G ^W YDV _Q ^R EVI _G NLI _G ^W YDV _Q ^{R N} RP _S IL _G ^T ID ^D I GTK _S IL _G ^S ITIKAEA _S ^T D _S KF CET DDNE IP ^N RP ^R _{G S} TKFFDPI _S ^N KLA IFFILD VLR IFFI QLNPFEKDLHKEKP _S ^V TIKFWV ^F F S TTT _S ^V TIKF YN ^T T _S ^L DY ^N _C ET GYN ^T DDNED K S ANT ^S E ^K KLNLVL N N EDLFI PRYR EVENPRYR NE ^L _{S S} N ^L AN SREPI KANE _S ^L N _S ^L RE ^L _S T ^L _S R ERTA GYI _S ^R ADI I _S ^{D T} F G ^D EL RITDL ^A N G YKFM ^{E L} R _Q ^T Q _S PRK Y YKFM N TA AT _G ^L DLN A VE ^P _{S S} I ^T M GLLAMNLIL _S ^G LVI _Q ^{E P} _{Q Q} K _S ^A _S ^F VDI NL _G ^T FY ^{L K K} VE _Q ^T K _G ^S D _G TLV ^R IYAK ^K T G D _G ^K TLTTIKIKWFMNENIADH ^K FE MKI QN ^A AHI F ^L _G ^K FE KE _C DTVKI _G NY ^AK E _C ^S DTVKV DYATAK HA ^L KK ^T DAI G ^V YV _{Q G} ED ^V _S KK Y ^E _{S Q} K ^D _G I _Q N ^A SKAIYVKYNYT _{C S} KAIYVKY _C ^K KNFN ^ML IE Q _S NHPN ^L Y GKLNKLT _S ^D VN ^E TD QL Y _Q ^A TE ^KK H _S ^Q Q _S DT ^G _S TDY ^E _{S Q} K GLV Y _Q ^A TE KKNT LIKLKKNT ^M KTFN ^L R GLLEKEN DVAA AEDIVLNWVT _G ^L E EIEK ^M KTY CTVL K _C TVLLIHL A A _G ^D IH ^I I SELIIKDHRA ^N TINFVLKI ^L G TVET ^S _G E TI DI ^R KDEEIE GNNKDI ^{Q D K} T E _G ET ^E E GRV YDA IKDDII ^N LIK QLTEV ^K D GVKT ^Q F _Q IK _G ^N QPYTEV ^K D GV RW ^K K Q ^K N GE _C ^F _G ^G INFYRW ^K K Q _G E _C ^{F G R} NY G _G YITD ^D _{S S} TY E _G ^L NAV _G ^Y ELIIV EIKVAA ^Y A QKE IYEIKV FD ^{F F} _G ^M YDDTNDAFD ^{F M} YDNLPTAV ^L IM ^Y T QVFIKKLADD _G ^Y NY GVDELI LKHLV _G ^N IDELI ⁰ V _G L _Q HKK ^Q _Q HKIR PI ^S _G F _Q TLDELDLE ^D DK ^E GLDTK KLK ^E ₀ E _Q EKTNYE ^T KAV ^F _{G G} L S _S DKE _Q ^F EKT YE ^R YA _Q ^Y K MIEVT _G ^{N N} FH G _G ^Y NYIENDK _S ^F TT ^Y _S KALTKKTKLK ^E O F R I E Y D Y I I M I N F R I E Y _S ^N Y I ^N _{S S} M D K D ^Q I Q A D _G ^R L K V R M F F N W T I D E K E I M P ^L _G FMINIK ^Q ATT ^Y _{S C} A N F E E I V _S D M P ^L _G F C A N ₆ ^W 0 ^{5 0} _{1 7} ^{. .} _{7 5} ⁷ 7 _{8 9 0 1} ⁹ ₉ 4 ₃ ⁴ ₃ ⁵ ₃ ⁵ ₁ ⁸

3 ¹ ₈

B ₇ ⁴

^K

LI KII KYETF I KII KYETF I KII KKILYLP A _Q ^S KKIKV VLF _Q AKM _G ^K LYLP QI _Q ^I LV KK I _Q ^L I _Q ^I LV KK I _Q ^L I _Q ^I LV II TRN _S ^D D ^I M A _S EHII RA ^K N QDDY NIHLFTRN HAKLP _S ^A IL _G ^D _Q ^R MHAKLP _S IL _G ^D _Q ^R MHAKLP _S ^A YM ^K F GDEE HE IYM _G ^K LFLP ^G L KIKV F KLIKYKIKV F KLIKYKIKV F KHLEYH _G ^G _G ^K A ^{N K} _G LKHLFTRN ^D A _G E S _S D ^L YALDEE CKL EYH _G ^D ILPN _G KHKL N _G ^S KHKL KALRVIMRH _S KALDE ^T T EKA _G ^E RVIM MEVAF _S ^D KAEL ^K ILP Q EVAF _S ^D KAEL ^K ILPN _G ^S Q EVAF _S ^D DLEE HF ^K T QADLEEY _Q ^Q _G ^{D K} H _{Q G} AT _S ^A KDLLE MV QEDI ELLFY _Q ^M EDI TAEI ^H MVN SDKKY LNTAERVIMRHEA RVD ^G L TA ^G L ELLFY _Q ^M EDI DIR ^F _G H GYT ^L TLRVD ^F _G H TA FRVD ^G L G E MVNHVL ^T TYDI _S ^H DK S VEKH GYT ^L T ^F _G H ^N LLKHKVAD ^{G E L H} KV GYDDKDL N _{S C} ^N LL GYDI _S EKKYKLN _G ^N LEDKDL EKKNKN ^N L _{S G} YE _Q ^{E L} DIR SEKKNKN ^N L _{S G} YE _Q ^{E L} DIR _G YT SEKKNKN LVELPEE _S ^S I _Q ^T LVEKHRIADKRYLR LPEE FL LTV HVLDNFL LTV HVLDNFL LTV VLEFLFDTET ^A E SKVLEDKDL RVL _S ^Y FLFD I ^K YVY YVY KI ^K YVY KRYYVLVLREA KRYLPEE ^S NVR SIIRKKDDYVLV T ^S _{Q Q} ^N ADD ^V LDIKI ^K SREKPT ^S _{Q Q} ADD ^V LDI SREKPT ^S _{Q Q} ADD MLTDKTIVVVL _S ^T MLTFLFDTEN RMA DKTI LW _Q DW ^F MLEELLW _Q ^N DW MLEELLW _Q ^N DW KDD ELKRKKLTKDDYVLVLR ^G PKK _S ^K I HN _S KDYLVI HN _S ^F K YLVI HN _S ^F KA ^S ETVNYKRYKA KTIVV ^V _{G Q} EIKE ^S ELK GETV K _G ^I _S ^K AN ^E RETFKK _G ^I _S ^K AN ^{D E} R _G TFKK _G ^I _S ^K AN AK ^K _{G S} DPK FVRRAK ^K D S ELKRKPFKA ^F VKAHK _Q KKEPEVKAHK _Q KKEPEVKAHK _Q ^E PE LI ^S D Q EIRKPE ^S ETVNY ^S _Q APK IKVHRY ME HRY ME TIKVHRY V ^F I QKYIL _S ^I FN V ^F _{G Q} NPK DF ^Y E SF ^E P _S LILI _Q ^S V _G VDK DILHET _Q ^K ETIK S P HET _Q ^K E PDILHET _Q K _S ^S LILD D ^G R T ^S DIL _G PK _S ^T LILI _Q ^S LKAA ^K YIL SLD EAVPII ^L _{Q S} LEAVPII ^L _{S Q S} ^{T S} LEAVPII YDK DE ^I D GDK _Q ^V EIYDKKYIL ^I KL SFV _S ^L FYLDLDE _G ^I FPKNLK _G ^E YD ^F _{G Q} VYFPKNLK _G ^E YD ^F _{G Q} VYFPKNLK _G ^E DAA _S ^K NIKKRPFKDAATLD DEKYNDH TNIK I IKDADVLVTI IKDADVLVTI DLDLLVKIF DE _G ^I DKRKFDK _S ^E NLVK P ^S D GDEDYWDLK ^S N EDYWDLK ^S NIKDA TH TEIF ^Y E ^E DLDL F _G TH NIKKRVPDTRLKTEI EP ^I RP ^D P _G D RP T V _S ^{G D} P _G DEDYW QEP RP IK ^E I SNMEA ^Q _{S S} L IK _S ^E _G ^I LVKIFKLAILKLMEA ML _S VK ^H L T Q ^K V _S ^G _Q EP QELKML _S ^I VK ^H L Q L _Q ^K ELKML _S ^I VK ^H L Q VRLKRNP _Q ^A VV ^L L SFVRLKTEIF PVHFYRNP E ^D NKEA ^D L G VRAETE KEA _G ^D VRAETE KEA _G ^D ALKLTV LKYNALKLMEA ^Q EK SFM P _Q DY LEKM ^D N Y QIV ^K HMA HLK ^P _Q D ^K HMALEKM ^D N P _Q DY ^K HM ^W HFYIK ^S P GI RNP _Q ^A VDL ^A AYNKTV G IMYIK _G ^S GYNKFDPI ^N RKF SVPD ^W HFY GYNKTV LTKL _G ^W TKFFDP EVI ^L _S YR GNLI _G ^W YDV ^R _Q IV QEVI ^L _S YR HLK GNLI _G ^W YDV ^R _Q IV QEVI ^L _S YR GNLI LD FVLR IFFILD FVLR ^V IFFILD FVLR ^V ITYKDLHKKLA IK ^S P GI STKFELDDLEKP ^V ITY STKFFDPI ^N RDA SK ^V PFEKDL SFN WV _S ^{F T} TTT _S ^V TIKFWV _S ^{F T} TTT _S TIKFWV _S ^F PFE TFI NPFEKDLHKN ^E T QLN ^D ELD E R _Q EVE NPRYR _Q EVE NPRYR ^T TTTN QEVE FN ^A FHI G ELDDLWVT ^E _Q FH Q _S ^L PRK YKFM _Q ^{E L} R SPRK YKFM _Q ^{E L} R SPRK _G ^D _S AVDIDL ^{A T} _{Q Q} ^P K _S ^A AV MKIFY ^L Y Q ^T MKIFY ^L Y Q ^{T K} KKVYV KL ^T FN G ^D Q ^P _{Q Q} KEDA K _Q ^I DAI _Q ^KP _Q ^{L V} KKV L _G ^K FE MKIFY ^L Y ^T Q _Q K ^AF HITA _G H S _S VDII ^N L QLIY _{G G} EDA AHI ^Q F ^L _G ^K FE D _G I _Q N ^A AHI ^Q F ^D _G I _Q N ^A AHI ^L I QF H KLE _S ^D VKETDH KKVYV DKLNKLE K H _S Y ^E _{S Q} K Y _G ^L _G ^V DIILDNRL ^L EDT K _G ^{E Y} N K _G I Q _S DT ^G _S T D GLV Y _Q ^A TE ^K H _{S Q S} ^K DT ^G _S T DY ^E _{S Q} K GLV Y _Q ^A TE ^K _S ^D _G D ST Q ^K H SDT _G ^G LV _G ^L ALNIKDHRWIT ^L Y _{G G} ^V GALNKLE _S ^D VTK ^L VAEDII GVLIIKD NFVLKI ^L E TINFVLKI ^L E TINFVLKI DAEVKDDIANL DIILDDN _S ^F TVET ^S _G K _G ^N TVET ELIKLVIVIHL ^I DAE SELIIKDHR K ^I DA SAI ^Y VKD GKLV KT ^Q F _Q I QPY TEV ^K D GVKT ^Q F ^S _{G Q} IK _G ^N TVET F _Q ^S _S ^I QPY TEV ^K D GVKT A _Q ^Q PYYEA D DK YEA VKDDI _S ^K L _S ^D YKLADD AA ^Y A QKE I YEIKVAA ^Y A QKE I YEIKVAA _Q ^Y KE AI ^Y D GFH _G ^D LD _G ^{E Y} N GINAI _G ^Y KLVIVYFIN FH _G ^D LKHLV _G ^N I DELI LKHLV _G ^N I DELI LKHLV ^N IN GIKKLANYVENDK KKLADD KEEEK _G ^N _G ^N _G ^Y NYV ⁰ KALTKKT KLK ^E KALTKKT KLK ^E KALTKKTK ₀ MINIK ATT ^Y _{S G} FMINIK ^Q ATT ^Y _{S G} FMINIK AT ^{N N Y} W AN _S ^F K FH ^D D GLDVVEKFFNW V G _{G G} P ^T V G ^D E Q _G DNE T _G ^N _G ^N _G ^Y NYVENVP TILKP _G ^T O F E E I V _S D M P _C ^L A N F E E I V _S D M P _C ^L A N F E E I V _S ^Q D M F F N T L _S ^Q T H T L _S ^N M F F N W T V D E P N _S ^I M P T N T L _S ^Q

6 ^W 0 ^{5 0} _{1 7} ^{. .} _{7 5} ⁷ 2 _{3 4 5 6} ⁹ ₉ 5 ₃ ⁵ ₃ ⁵ ₃ ⁵ ₁ ⁸

3 ¹ ₈

B ₇ ⁴

DA _S ^I EHKKIKV NVLPLIKKILYLP ^S F _G ^D _Q ^R YYIRL V KA ^L DKEILIKP SDE ^N III ^K RA _Q ^K DDYLV II RN ^D A SD ^I M _Q K SEHKKIKV ^D NE II _Q ^I RT SLY A _Q ^H V ^K V _G L GLT IIKKD KH _G LYM _G LYLP A M _Q ^S YM ^K FT GDEE E I RT ^K N QD ^D L CA ^S ITLF LPV _G ^T TAEI ^R F GK ^E K GA GA _S ^K LFTRN _S ^D D _S ^I EHKHLEYH _G ^{G K} H GA ^N II M _G ^K LFLPV ^D HLFY G _Q ^{Y L} _{Q G} ALDERAEV ^K VE S _Q ^H EEHP RHF ^K TKH QAKALDEE HLFI KPT _S ^R LNEYN LP ^S K Q EPA ^W DI GR ^A NH LNDLEEYH ^D HE G _G ^K A ^N IKALRVIMRH ^K _G L S T _Q ^Y GLDLEE VNHF _Q ^K AKALDE ^R NV _G ^T Q EVPLI TANRTA _G ^KI V G _S AILH FIF _Q ^V _G ^K RP ^L _{S G} KY _G ^L ERVIMRH _S ^{K K} TTAEI ^H M SDKKY LEEYR _G ^Y LVLV IMPNTVI MIYYDF A _G ^K AD ^E TA S _C ^N LLE VNHF _Q A LKHKVAD ^G LNN G AERLIMNA ^S LLN GYEI _S ^L MIVLEML DIEPLR _S ^T NV SN _Q ^T DI ^H M SDKKY LT ^N L GYDDKDL N _S ^{E L} T C LLE MVPN ^I M _Q ^N SEH LIEKHEKNY R IR SIT ^A E _G Y SKLVEKHKVAD _G ^G ELPEE ^{S L} _S I _Q ^{T N} YDI _S ^L EKVLE KVDA ^N E S ^T E S LN _G ^Y VI ^V RKE Q TEEA VLEDKDL N ^E LV S _C VLEFLFDTET ^A E _{G S} KLVEKHRVNY ^N I VLDTK DITDF _G ^N N LLDAKA _S ^KL N QL LRVL _S ^T KRYLPEE _S ^S I _Q ^T LEDKDL ^K _G L KRYLP S T MLTFLEE VVKLTMLTFLFDTET ^A EKRYYVLVLREA I SKMLTDKTIVVVL _S ^T KRYLPEE ^D A SDF _Q ^K AKDDDVFD ^K H GA _G ^G _Q ^KL R C L ^{T M} NN S _S RL ^L EEY QEW RKKRYKDDYVLVLREA KDD KRKKLTMLTFLFD LVRH NE ^H NYVRRKA L _S ^T KA ^S EL VNYKRYKDD ^R LN KAKEK DFIKKAK ^K DKTIVVV S ^Y VLV ^K H GA _G E ^L AKA TINH ^T LE R QEKFID ^S E SN _Q ^V _S ^{D R} _{Q S} SELKRKKLTAK ^K _G ET SDPK ^K _G KTIRH LNHYIT ML IEN RYPE ^S DFVRRKV Q EIRKA _S ^T V _C PE _G ^A _Q ^E SF ^G RPE GPV ^F _G ETVNYK ^L QDPK RRV ^F ILI QKYIL _S ^I FN ^S ELKNH _Q E VT _Q DPTI E ^T K S RTI ^R L QV ^Q RY _G ^Y QA V _G DD _Q EIK _S ^S LILI ^S DFV Q EIRKK _S ^S LILD ^G RP ^{K F} _G E IKYK _S ^A KKNLLLL ^E D SNT _S ^A RHIILEEF ^N K QF QDP _Q ^T EA DKTYI _Q ^T RIKAY NI PFTENL DKPFKYDK YIL _S ^I FN ^I DD _G PV LILI ^S AD Q NVL ^T Y S DAAEEILTEKLRLA _S ^A LK KR E DAA _S ^K LD ^G RYDK DE _G DK _Q ^V EIK _S ^{T E} _G PDAA _S ^K NIKKRPFKYDK YIL _S ^S IKLT DLDLDD LRVLVRKY ^L IIY QFIE IF _S ^Y F _G DLDLDE ^I DD GDK _Q ^V EIDLDLLVKIF E DAA _S ^K LD RY TAEIFE _G ^I VLIRD RII ^L A S PI F ^Q L ^L LTY IKKRPFKTH IF ^Y F _G ^E DLDLDE ^I TEK GLRVRRIKPPNIKKKNR H A _S V _S FIN ^E TN SNLVKIF E IK ^E ITE SNMEA ^Q _{S S} L QV YNVRLKTEIF ^Y F _G ^E VRLKRNP _Q ^A VV ^L LTR SFVK ^E TNIKVVIRKVRLKTIKNY ^D R ^K A _S ^Y YN ^S M SE R ^K _S NLTKRKN K _S ^{T H} _Q F QAT _S ^{F E} ENI SALK PL _C KFALKLMEA ^Q _{S S} L ^G RALNIMNID ^V _{Q Q G} I IPD FYRNP _Q ^A VV ^L LALKLTV SF FYIK ^S PLKYNIR GI KFAL ^L KTKINY ^V _G P HFYREA ^F PNI R N _Q LMEADL _Q EI _G ^W Y NP ^I _{G S} F ^L TIHLPLP I _S TLA ^W H GYNKTV YN ^W H GYNKFDPI ^N R SVPD FYRNP FK ^H KE SYI ^A E _Q LNKK HKRKP MYIK ^S PLK GI KF TYKDLHKKLA ^W H GYNKTA ^I KP E ^V I STKFF ^E D _S L _S ^E _G ^Y S _G ^S D _Q ^D LEN R ^N LKPR _Q ^{Q L} Y S _G LEIRLD _S ^N DLFI ^V I KFFDPI ^N R SVPD ^V I STKFELDDLEKP TYIK ^S _S F GDD _S ^Y F _G ^E NPFA DLVMVKT IT ^A _S T GNPFEKDLHKKLANPFE HITFI ^V I STKFFDPDRL L NE ^A NAKRVFL RD QDLIFK F ETYLDIKKI DI ^N L SKL N KP N ^A F VDIDL _G ^A NEFEKDLKRV ^L _S F ^T Y GNP D R _S ^L T ATEAEKE YVKDA ^T F G ^D ELDDLE K ^P _Q HITFI ^T F G ^D _S A VYV KL N ^D ELDIFKYN IDT _S ^{Q A} L SFR _S ^F _S ^D VYF AFEHHKL ^R N Q DKKETI _{Q Q} K ^A F SAVDIDL _G ^A I _Q ^KP _Q KK QKEDA K _Q ^I DA ^T F GE A SVDRLDH KLDH E _S ^D VKETIK ^P _Q HF KF DH QK _S ^A _S ^F V ^Q R A _S VPD ^L TA GK ^I RV KKT QPF _G ^T PE ^T DEIDEN _G ^T QAVLEKEL LDWIT Y _G ^{L V} KKVYV GEDA ^D K _Q ^I DA ^L KL G _G ^V DIILDNRLDY HRANL _G ^L ALNKLE _S V ^V VILA ^L Y GA ^E K DI LP _G ^K DLTYFVVF KET ^L Y GALNIKDHRWIT ^L KKI _{Q G G} EDLPLKKP ^L _Q D S _S ^G DKNI ^K F SDT AEVT VIKA DIIHL DAEDIILDNRL AEVKDDIANL ^L Y GE IVD N _S ^I ELIIKDHRWIT ^I D SELIKLVIVIHL ^L NKLEI I ^I K SELIVI SEDIII ^N F SDL _G ^A A MI ^I HKKI _G ^A EYDL _C ^T SDLTM FIAVK ^T KKV SIVL DKE _G ^Y IYEA NLYEA DD ^I K LILKDHK KL _S ^Y _Q ^E I _G ^Y EKDITKL _S ^F FLNNW LF LDTK ^Y VKDDIA GKLVIVIHLNAI _G ^Y FH ^D DK GLD _G ^{E Y} N _S E GIYEA IRDDL _Q ^T DAKLLADLKDIDHT _S ^L TETY _Q ^A AA ENDN ^F NAI SKKLADD DK NKKLANYVENDK I _G ^Y DLVITK LYVW ^{H 0} E _G LD _G ^E _G ^Y IK ^N W V ^{F K} K DEAN _{S Q} LLADDDDIN ^K T K QL E _G ^{T N} FL G _G ^Y ND ^E F LKMIWL K ^V _{G G} RLARI _{0 G} ^{D K} E ^N K ^Y FH ^{D G} KV _Q D _S L _S T _G ^N _G ^N _G NYVENDK ^{Y F} T _G ^N _{G G} P _G ^T M F F N T L ^Q _G DNE ^N T S T H T L _S M _G ^{T N} _G ^Y FHDYIWIT VFFDWH _{G S} ^H VIIF WYDLKK ^I N _Q ^D GEA O T _S Y F I M F F N W T V D E A N _{S G} N Y I D K A N L M I L K P Y E L R E D L M K L L I E K I H ₆ ^W

0 ^{5 0} _{1 7} ^{. .} _{7 5} ⁷ 7 _{8 9 0 1} ⁹ ₉

8 ⁵ ₃ ⁵ ₃ ⁶ ₃ ⁶ ₁

3 ¹ ₈

B ₇ ⁴

I _S ^C _S ^R LRD _Q ^L Y _Q ^I LRV IET _S ^Q _S ^A FA _Q ^S VTY K KVYNKANNTKKIRALPVAILIKHEKHIMPNYA RY AA MLATEK DH ^L A IPLAK ^A K G I _Q ^I RTTEV RVIII F VLLRKAEAKM VLKE TF _S ^K KL _C ^F FYVIMD _G ^A D KPV _G ^T KY YI ^I L GF ^R NE VKNT PP _S ^I DYMI QY LL ENLHEIL ^L Y GA ^G _G KHV FPL _S ^I MALF LKEVP _Q ^S EHLD ^K _{Q Q} K _G ^Y _S ^N A VE ^D L SA ^Y I SFLKV VV RL _G ^P IRKKTTN ^L _G KDEI _S ^K DLN HHLLY SDDKHHK RH L _S ^K HKALEYIMPN _S ^D FY VDL ^G APY GDDK AK TVKNETK ^I V LIVI ^R KT RALDE GIL DLNEYE ^E V SA LNRLMVVL ^N LDY A ^R _G YKDNEEKHW LN _S LYKA ^I A _S E A VI ^L DL SVTKIT TADRLE _G PN ^I PID SLLTAEE Y _G ^G _Q ^Q _G ^L AV EFDEAN _S ^L PV L ^N _G D YD DYF ^F _Q ^I F QFLA KVI _G ^Y EKDDIDLF LLN IMVLEAT LLI ^L EKN SRV AKPTVL _C ^A _G ^A KVVRHE IE I _Q PY _G LAEL MVNY YDKHDL _S ^D DPLVKREEPTI HK _G ^K GI AHID ^L RNLL KI QTMEI D ^G YVWDL _G ^N YDL _S ^L EK ^K LA _G ^N SEDLVEEKEE HLF MLIILLK _G ^N YR IK KHRE _S ^D TEIKV A _G ^{N N Y} FL _Q KH LIDKH G _G ND ^D KV KI VLDVKRV ^D A SDF LDIPFD _G ^K A M _Q ^S KDDNYILADP _S ^D IK AEFKKNV FNWH ^G _S VI SLE VI KRYLPDL ^N LV R FLLVRH _S ^I EHRATETK NIA EI DDT E _S ^{N V} R AF S PI EE ^K H GA ^G _G VK G L _S ^Y YVTI HE KKKLDV _Q ^S _S ^S VL RL VYL ^L L QFV _Q ^L YK _S ^{K L} KPY EN FLTLL G T ^V RR _G ^E QNITKE KDDEVFDRH ^K EM DDD F ^N I GLVEEIKILTEK _C ^E KK RIKDPRFLF ^V P GHN _Q ^S I _G ^T AIL A KLVNH ^T _Q KK QL A ^KL K _S ^N SL N _S ^K L ITND R N LE _S ^G KKVLHKFK KDT K _G ^E _G ^Y _Q ^A _S ^K K ^K E S TVKYV ^T K SAK _S ^RG _{Q G} DL ^K NF ^K T Q D _S ^S LKTE ^I L GVV _S ^S K KF AIETIEIY ^E HR S KFE _S ^{L K} D QLDNKE PD ^T E LK E _G ^E TPE I L _S ^S MLKLK AD R K K _S ^{K I} E TV ^D N SNT YV ^F DPV ^S _{S Q} N E _G ^G EL ^Y NDL QVFYKMKNY _G ^N HD G ^I N Q I ^M IVT SKK L _G ^F A ^I _G H Q VK ^E F I NTARV ^L _G N GI ^E A SND _Q ^E EEEI K ^T _Q DP SLMLL RIK _S ^A RK ^S _Q VLILT SL D LR IVNLVKEEID KY P PEKFEDDILP YDKKNV _Q ^T TEKAKYDK ^K Y QLE _G ^I VV _Q ^T TE ITA ^L KYL QPLR KD N ^A ER _G ^K SRN ^I AT _G ^K E KK KI RD NT ^S _Q KA Q ^L KRRKVYLFKEVAEKILLRVLRDAALDLKRKE ^A E STLE ^K Y QFFNP _S ^{I F} A EL _Q YTDFYKPDD DLDLDD ^I VVIMDDLDLNVKNYEAVVRFDDL ^F K QI ^L K S _Q PDKK ^S D I KE GL ^K E GVE KEAKMETMTRIRTKEIFE _G KKNRITHENNDID VL AL ^V VP ^S N GDKTV _S ^R I ^A E Q FAKFDL IKD KVIEWV PH IKAPNLKNY KDKTVA ^F KL _Q ^{T N} LK ^L KLLRE _S ^E L PLLPA ^L DNK S MRNKVRLKTIKD ^V KTV Q T RLLMNP ^L _{G S} FKRY ^W H _{G Q G} YKK ^A NATRALE SDLIF AR _Q TFL KL ^E A QVY A NLF _S ^G D _G ^R KN ALDIMDI ^F P _G ^R D _S ^V LEYRD VRR ^K HY YI NIPD _G ^I E D ^R I S EY FFREA ^I _{Q S} F HFKE ^S NE ^V I ^K LDF SL YEYVN ^{I G E} VH M _S ^F G _{G S} LK KEL _Q ^{Q R} I SEH _Q ^N D _G ^E F ^W H PDD ^M NF SEY _G ^W Y YI ^S _G DK SAKR ^I _S T ^S T G _G IA ^Q _{S S} F _S ^N _G ^L S ^R L GNNRV _G ^K F V _Q ^S V LT AE TFIIERK RR ILLN ^A _G Y ^N KEN YE _Q ^T NDALEEA _S ^VH DE Q DL V _G ^N _S ^{V S} _{S S} YIE SL ^V I STKFFE ^S DKLLK I _S ^N FFDLIF GKRVEF _S ^V TKD M F ^V N D _Q ^E IPL _G ^E VI QE _Q ^{S T} YID GN VK NF VV KKIAIYE DR _S ^R LRD ^L Y QY ^I A QLRVNPFE ALFKFANPF ^A F _Q ^{E N} PLKIK ^L I S K ^S V QI _S ^A _Q ^K _Q ^L _Q ^S VV R _Q ^E RKMAV DH AA MLATEK NE ^S N QDLF R A ^T FN ^E _{Q Q} AEV ^S _{S Q} V I _G ^Y E ^M LHKI AA _Q ^L LR _Q ^K _S ^R KTKVF KF _S ^K KL _C ^F FYVIMD ^T Y GKP N ^D _{G S} V _S ^L P _G EPN K ^Y EIDH SFD EVDDLE ^N Y GI TE IIRELMLRT L NLHEIL IET _S ^{Q A} L SFA _Q ^S VTY KMT _S ^{S V} PL L A ^L Y GA ^F A Q IKKITT YL F ^D L ^{G R} RNV ^L Y Q D ^F L SRL ^P E GIRKKTTN DH IPLAK ^A I GDH ^D _Q I GHI _S ^N V _S ^L DIVA _G ^Y NLDDVK ^K I QT GH L _S I _{S G} EDD _S ^P TVKNETK ^L A HV FPL Y _G ^{L K} T GKILHKKYLTEFDWLTYIKA GE KLAL ^K KD LYKA ^I A _G ^A D EI _S ^K DLN _G ^L KFDDIDDLKKFYE PD RVE _S ^S YL DLHF _G ^WR FYD _Q DD _S ^A SKVFE DVL ^{N I} F _G D ^L Y GA ^G _G K HHK KT VVIIK ITVPKPE ^M I GARH _S ^T _S ^N L IR VILATN K N DKI ^D YF LA ^L _G KD SDDK QPY ^F _{Q Q} F G LL ^I V SELIVI DL _G ^R IL _S ^I E L _G ^D DVNFFNI IY ^V IN AY K _Q ^R Y _G ^G D DAAHID ^L RN EI YDA VI ^L _S VTKITYD _S ^{L Y} V GNL YIAK T ^T A SN ^V L _Q N TY ^D A S ^E PY GKR ^Q T E KMKHRE ^D _Q TM STEIKVKVI _G ^Y EK ^D DIDLFPAVADD _G ^D FI ^G K GMAKN ^E T _Q NE ^A L M _S E GAEHM _Q AK ⁰ DK N _S ^D LRR _G I ^D Y GKPD YEAEFKKNV _G YVWDLKIM LL ₀ LL DLH L ^Y FHI ^Q K SVHIPNF FD KITR E ^{N V} RKILAEL S D VKHK KT F _G ^E IA _S ^Y ED N O H F P N I ^M R G K ^K LYK DT Q K V P _G ^{S G} D G M ^N D S V Y L ^L L Q F V ^L _{S Q} Y K _S ^K M _G ^{N N} _G ^Y F G N D ^{Q D} K G _S V I K I M ^N _G NY LN G _G ^N N W T _Q ^V N R T N ^A K G M P P E K A I L ^N YM G D R T ₆ ^W

0 ^{5 0} _{1 7} ^{. .} _{7 5} ⁷ 2 _{3 4 5 6} ⁹ ₉ 6 ⁶ ₃ ⁶ ₃ ⁶ ₃ ⁶ ₁ ⁸ 3 ₃ ¹ ₈

B ₇ ⁴

KYTE PIAEV I ETEDVVKPY I ETEDVVKPY KPY L _G ^H ETE I _S ^F K _S ^P E KKEE _C ^Y _Q ^L PEVFA L _G ^{H D} NKVIAIL _G ^L L _G ^H KVIAIL ^L I G L ^H ETEDVV G KVIAIL _G ^L NR N _S ^D IKLDV IILE E L ^{R G} K NR _{G Q} YY FT NR _G ^{D R} N QYY EVLFT NR _G ^{D R} N QYY VLFT KF _G ^D _Q ^R YYIMLFY QIDI _S ^L K _G ^Y P _G ^V _G H KFIKVI ^I EVL Q VKKI KFIKVN _Q ^I KKI KFIKVN ^I E Q VKKI KKIKV NEL KHEKHIMPNYA KK EE ^L V SA K RTEE _S ^L A M II T _Q ^K AHA ^G E GR KAEAKM VLKE II ^Q RTDE _S ^L A M GLFLPPN _S ^{D S} KK ^Q RT LPPN ^D M S ^S K I ^{Q V} _G LFLPPN _S ^{D S E} R FLPV DL IPR _S NYII YILFKRKVL ^F _Q II _G LF QH YILFKREVL ^F _Q I ILFKREVL ^F _{Q Q} H ^S M _G L QHLFT NV ^N YH GKE SA _S ^Y FLKV ^D APY EHLDEK Y _G ^N TI EHLDEK DY ^N _Q H Y GTI EHLDEK DY _G ^N TI KA E _Q ^R VKP NLDYVDL _G DNA KANEYK ^Y D G AHPL KANEYK _G ^Y HPL KANEYK _G ^Y HPL DL ^L D GEYR ^H E G VPE GYKDNEEKHL NIIM _S ^D DAL DLENIIM ^D A SDAL LENIIM ^D A SDAL TAERLIM _S ^I ANY AV ^AA EFEEAN ^L DLE S TALK V HLA _S ^T TALK V LA ^T D S TALK MV LA _S ^T VL _{C G} KVVRHT I ^L M SEK _G ^K A LN DI ^L M SEK ^K H GA IDI _S ^L EK ^K H GA ^N LLD ^P MVPNWD KREEPTV ^E LD KHRVRH _S ^I EL ^N I GYEKHRVRH ^I LN SEL _G ^N YEKHRVRH ^I LN _G YDI _S EKVL KD SEL LVEKHRVDY _S ^Y E MLIILLK ^N HK _{G G} ^N YE GYKD LVDEKDLNHE LNHE IDEKDLNHE KDDNYILADPI VL LPEEKY ^N VLIDEKD GE VL EKY ^N VL L LPEEKY ^N VVLEDKDL ANI _G ^E RATETK LLFDAD _S ^{K Y} LPE DAN ^K _G E V S KRR _S ^Y FLFDAN ^K _G E KRYLPEE _S ^D DKRL S KMLTFLFD HT KKKLDV _Q ^{S S} NIA RR _S ^Y SVLE MLDYVLV ^S NF ^K KRR _S FLF Q MLDNVLV NF _Q ^K LDNVLV F _Q ^K VEEIKILTEKR KDKEKTI _S V L _S ^T KDK KTI _S ^S V ^T M DK TI ^S N _G AK _S ^Y _S ^K SV ^T KDDYVLV ^K L TND LR KAA KVE ^G L _S K G AA ^E K SELKVE ^G L _S KA KTIRHRHL G D ^S I SLKTE _G ^I VV ^S K SE AK ^S ELKVE _G ^G GE ^E T KAA _S ^E EL LMLKLK _S PE _Q ^{F T} LLR _G Y AK ^F DE LLR ^E T K ^E T AK ^K D S ELKNHPYD T _G Y AK DE Q ^T LLR P ^{S Q F} _G E VKYILI YND ^A RPE _Q P _Q ^T E ^F _Q VI ^T _G Y Q RV _{S Q} DP _Q ^T DLLR QVFYKMKNY ^D A GHDVKL ^E P _Q VI _Q ^T QLV _Q ^S RKI _S KVKL _Q ^E LV ^S VI _{Q Q} RKI ^A RP SKVKL ^E P QLV _Q ^S RKI _S ^A KKILILI _Q ^S _S ^D NKTT NLVKEEID KYILNYEARKKPKYILNYEARKKPKYILNYEARYDK YILRI TE TE YITA ^L RYLKKP TLD D LD YDTTFD LE _Q ^K FFNP ^I _Q PLRYDT S KLKDAKLDE _G ^{I F} T LVDAKLDE ^I D LD YDTTFD ^I D TLD DVA _S ^K LD E _S ^D FY G ^F T GKLVDAKLDE _G ^F KLVDLDLDE ^I T GLR VRFDDL N _Q ^F PT LNLK ^I _G K SFKRI DLDLNLK _S ^I FKRI DLDLNLK ^I _{G S} FKRI TH NIKVV _G ^E _Q ^R _G ^L AL ^V VP _G ^S DK ^R DLD STEE ^K N DEVRKTEE ^K N KDEVRKTEE VRKIK ^E T SNLIKRKKPT WH _G ^N _Q NATR ^N M QLEIKL _S T ^I K SIDKI T _S ^I IDKI KL ^K N ST ^I KDE SIDKI D VR TKINYPII GYKK _S ^A DLIF Y L EAKRN ^R D IKL _{S G} F NLMEAKRN ^R D I GF RNLMEAKRN _G ^R F AL ^L K QLMEADLLV VI T F ^N H ^I RN Y _C ^M NPIF NF ^I R SLFYRNPIF ^I LFYRNPIF ST _G ^{S K} LD ^Q _S N ^L _S LF KHD F ^N EK YKHD ^N NF _S ^N NF HFYRNP E L _Q ^S NRV ^K _G IA GF ^S _S FP _G HH QV T _G ^W YKYIP _G ^{S N} _Q F ^W H GYKYIP ^S F EK HYKHD F _Q EK _G ^W YNKTV ^L F _S ^I EH G ^N _{Q S} PLF _G ^W YKYIP _G ^{S N} PLF ITYIK ^S _{S G} NEE TYIDD ^E V QIPL ^E L GLI FFNA ^A _S PL QV A KFFNA _Q ^A V EA IKFFNA ^A _{S Q} V GN IVK V ^V IK K ^M AADLPL ^Y E SFA ^V I S FAADLPL _S ^Y FA _S ^V FAADLPL ^Y EA _S ^V TKFFDPDK ^N I GL SFANPFEKDLKR ^{K L S} _S IK _S I _S ^A _{Q Q} ^S _S TF QNPD DHI ^Y K GE ^I _{Q G} LHKI Y F ^E EL I L P N _S ^T D Q F _S ^E I _S ^N V _S ^{L E} EL ^E I D L P FN ELDIFF ^K T QA GI ^N L SV ^L P N _S ^T S ^E EL I V _S ^{L T A} _G D _Q ^{D L} Y AEVDDLE _G ^N I _G ^T K _Q ^A N _S ^A DVHKKY _G ^{A T} F GK ^A _{Q Q} N ^A F SDVHKKY _G ^{A T} F GK ^A _Q F _G ^E I _S ^N QN _S ^A DVHKKY _G ID _Q ^P K _S ^AF HF SV ^N LN S _G ^G E GA _Q ^F ITTKIIE TA VDLRK IE RK H KV _Q ^A V R _C ^L IVA ^Y IKK GNMDDVKH ^K VDLRK ^L IE EITVP _S ^L DH ^N TKKVDL G DEITVP ^L D S Y _G ^{L V} K GEDNPL _Q ^T TEFDWLAYIKV ^T DH _G ^N S YV ^K E _G EITVP _S DH ^N TKK G ED GKLKDVTLT V _G ^K KLKDVTLT V ^K E GKLKDVTLT _G ^L K NKLAI ^A E YE PD EDILYIAIF ^L Y GDIEDILYIAIF ^L Y GDIEDILYIAIF V _S ^L EDIII ^N E _S T SEA PE ^M I GARH _S ^{T N} RVEN _G ^L DI SVINL ^I KLIVKN N NI IY LPNAL _S EK ^Q KFIT KLIVK ^Q KFIT LIVKN FIT _S ^I ELILKDHKTL _S ^V KT ^T A S NE ^{D MS} EY ^Y LE _S VHLF _S ^I EK LE GEL _S LKKKL Y L _G ^Y DL ^D _S VHLF ^I K SEK LE ^Q K SVHLF YAA RDDLKLT SLKKKL Y L _G ^Y DL _S ^D LKKKL EAI ^Y I T _Q ^V _G DLVITKRY MAK _S ^N _G ^E AEHM _{Q G} KP ^E L QFAED NRKDN P _Q ^E FAEDHNRKDN P _Q ^E FAEDHNRKDN KILADD DIVRR ⁰ NF D KITRLLKLE KTI KLE ₀ KF ^E F GIA _S ^Y EDDYMKNTA ^Y FH _S ^H DI GNY IRDRI NTA ^Y FH GNY ^S DIKAI KLE ^Y FH KAI K H _G ^D YIIRK GIRDRI NTA _G NY ^S DI GIRDRI M _G ^N _G ^{N Y} F GNYI KNKR O M P P E K A I L E N R R M A F D W T _S ^G D R W I N M A F D W T A D R W I N M A F D W T A D R W I N M F F N W T I _S ^Q V V N D ₆ ^W

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T _Q ^V NE _S ^A E KY _G ^D _Q ^R Y _S ^I IKK _S ^D LY VA _Q ^E IEAT _Q ^L YKA KKIKVAVVAD _G ^N TKKIKVDVVVL _Q ^K DKKIKVDV AEHM _Q ^M AKKKIKVDVML RKKIRFLH II RA EVF AII RA EA LII RA YKITRLL KI _G ^N _S ^{Y L} MKH G EAE FM _G ^Q LF _Q ^Y _S ^I LF _Q ^Y _S ^{I G} L FFM _G ^Q LF _Q ^Y _S ^I SED ^I I T SI ^Q R GLF _Q ^Y _S ^V EAKPT T ^F LLRRF CDF LV ^K K QV HHLFTAE ^L VL _Q ^K NFM _G ^Q SA FTAE ^L N _G E SLNI AIL ^N YMN GDRT EHLFTNEVKPLL A ^D E CYLKD _S ^E FKAV KALDELPPN ^G L GE ^F HHL CKALDELPPY ^Q HHLFTAE SKALDELP N ^I EHLRY KA ELPIALV DLNEY VLNI EY VA _G ^Q _S ^S NDLNEY F _S NV NL ^L D SEY AEV ^S FTR Q I ^L VLNRAKI QTIDATRD TTERL ^R D Q NY ^S DLN SK _G ^Q DK ^R R GKTAERL _Q ^{R L} V ^I M SEH ^E K GIEVTEKAKL ^Q _S TVERL ^R A QHNDVAPTAERL ^R E Q D TKKR ^H AE I _Q ^N A IKKL ^N LLE E KD ^T LK LLE K _G ^H GYDI ^L K _G ^H SIM ^D A _{G S} ^S V SDVA ^N LL I _S ^L IM ^D H NLLE _{S S} A GYDI ^L K _{G S} IMPN _G ^N L L ^M _Q LY _G ^N YDI _S ^L IM E ^F T SYEI I _S KR ^D AI S _G ^K VE LIEKHMV ^S _G YD KHMV RLIEKHMV LLINT ^E D CI LIEKHMVVL _S ^K T P E ^G I VLDDKEK ^K H _Q LIE GA ^T L QLYVLDEKEK ^K HER GHE VVLDEKEK G NEET VLEEKVKNYF _Q ^K A _C ^Q E _S ^{A T} _S RD KD KRYLPRVRHERRTRYLPRVRYT _Q ^R E ^N D S FLYAKRYLPRV A LKLEL ^K _Q A ^S A _S ^L AF QKK _G LPVY MLTLLDLNHERVMLTFLDLNDK ^S KRYLPRV D _S MLTFLDL ID _G ^K MLTFLDL _S D _G ^G EL REPEFDT KDDYVEEDYT YVEEDNK _G ^G TN ^R YLE QKTF KDDYVEE H KI YFAALKK ^G VH G _S ^D FL ^{Q N} KDD KA KFDKDK _{G S} DKFDKIVN ^Q KDDYVEE S A DKFE PI _Q ^N HKYF KV KFD _G ^K A _Q ^T RLRLH R _S K ^K D S EIV NKD ^K A SK _S ^K S LDKKAK ^K E S EIVRHE ^A E ST RLTFD ^M K GHE _S ^K _S ^I _Q ^H PE ^A ETL _S ^S IVN _S ^Q PE ^T EIV I _S ^K K _S ^K GETI ^S EIF SRNEEPE ^A EIV E ^L L QYIWP PE ^A ETINHEAVRNNPIDVAIYE V ^F _{G Q} DPLKTEIFIV ^F EPLKTV ^F _G ETI IMYNLL _S ^F V ^F _{G Q} EPLKDYTL TYEYIIEKLAV K _S ^K LILTILRNKEK ^K _{Q S} LFLTILK ^V F Q ^A V EPLK GK ^K _{Q S} LFLTI QLLAIKAK _S ^K LILTIKDKM _S ^T YV YA TKTF YDP YH VVF YDP NNYV TP YDP YH NKRY RT _S ^D KE ^L K QILVNL DAA _S ^K LV ^S V QRK ^{V Q L} _G DAA ^K YH ^S VYP _S ^L LYDP SLV _Q RL FDAA ^K YH SLV _Q ^S IRLN _G ^E L DAA _S ^K LV _Q ^S _S ^S IVRRRVL ^{E K} HL D KLDILNY _{S S} LD KLDILNR ^Y Y SKKD LDIL NNRKNV _G ^A DLKIDILTEI RLT _{Q Q} ^R K SKDD ^P K SK T _Q ^L ELYN L YFT _Q ^L LYN DFLPFT ^L K QELYN R TEKMTIELYN RN ^R K GRNALRELLFFD ^Q IKENNE ^I D G R _S ^L KRIK _G ^E NNE _G ^I L ^L N GN IKENNE ^I L GVV NE TIIR _Q VRLKTLK _S ^L FLPFVRLKTLK ^L EVL SKKK ^A IKENNE _G ^I GIRLKTLK FDK ^I DPA QIHN VRLKTFKRK _Q ^V EI RF ^AR _{G Q} ^RK HF S _Q K ALDIMIKDEIL ALDIMIKDRKIPVLDIMIK LDLRIRF ALDIMIKNYPLD KL ^D L SIL R Y _G ^G _S ^E EN TR ^W HFYK IDKKK _G ^A KAIDFII Y L LAY _G ^W A _S ^R _G YHKN _Q ^E RRIP ^W HFY GYHKNEAK ^A HFYKEI G _G ^W YHKNEA LM _Q ^E EE ^Y V GM ^W YFYREID GYHKHEA ^L E G _S F _G ^K R _Q ^K LHLRNI ^D YE GKID DLNV FL RVILPYK YKK ^V IKYIN ^A K SIFII INPI ^N TL SAN STKFFK ^V IKY F VFP ^{F V} IKYINP S _S TKFF KYD ^K KL ^V IKYINP _S ^L STK FK EV ^L F SF KHL _G ^A VP ^G NPFAAP ^S F G ^N TL _G ^A _S TKF SAN NPFAD _S ^KS F G LDNTNPFAD _S ^K _G ^S KET ^L _Q ED QAEVNPF _G ^F DP ^S D GDKKYK ^A DAE QT TR FD ^S _{G S} F KLPRFLF RRKF AN ^D K SLMK ^G N QAE L ^T D EEP _Q ^A VFP _S ^F EDP _Q ^A L G _Q ^{F E} ADLPLDNT ^{T F} D G _Q ^E ADLP ^N KI SENK ^T FD GN ^E EDP QADL VIHHFF ^T D EDPK G _Q ^{F E} FVPVT LHNRA A _G ^W K _S ^R IK ^A _{Q Q} T KTEILA _Q ^S IK ^A _{Q Q} T ^A DLI SM F ^N ILAE _S ^E N ELT _Q ^L EKDLDY ^S M ^N IILIK ^A _{Q Q} T ^S MEIKKKLIK _Q ^A T M SF _Q ^E RLKFMEADH ^{E N} T _S F ^E I QI _S ENKDH _S FRILNY DH T ^{S N} T ^S F _{Q S} ARP AK LKYD ^L Y _G ARVHKKKL ^N T AEVHTW ^{L K} HLRIEI VFI ^G NK _Q ^I SLAHIK ^T R QRKR _G EV _S ^K KK LN ^L Y _{G G} EV _G ^K KK IA ^G _S ^N CI ^L Y _{G G} EV ^K AEV GKK Q ^{S I} ANDX ^L Y _{G S} EV _Q ^A GEV _G ^K KK LDI _G ^A D APYLNWPE ^R I SR K _{Q Q} KTKK ^I KIDDD ^I D QITW _G ^Y _S ^L DD ^V D QIIIE SELIVKKDIAYI ^I KID SELIVKKDK E _S ^{F I} KIDDD _Q ^V SELVVKK FK YEI ^I KIDDD ^V P QI SELIVKKI ^N RNF F _G ^K LIK EVYIAT SKEALEF V _S ^V KLLEYEK IIVYIIE YEK IIVYV _G ^E L YEK LD ^S D GA YEK MIVHKKET VIL _G ^S KK ^R R SDKKYYPTL _G ^Y EID K E _S ^F PVL _G ^Y EID NTY ^{E D} _S PAL ^Y IIV GEID DRFE ^F F QM _G PEL _G ^Y EIDDLNVF TEMKL L KLFAEKD _S ^S V _G ^E L KLFAEKD _S ^S RDA KLFAEKN ⁰ N ETKKE KLFAEKNITWVT ^T LDN GFADLFEML _S ^D F _G ^L T N I _Q ^L ₀ F _G ^I K KRKK ^N T FLPLTTY _S ^E FL T FLTDIA L ^H YFELIDA KT _S A _S ^E _G ^Y NL RDA ^N T SA _S ^E _G ^Y NL ^L K _S ^K PY ^N T FLT SA _S ^E _G ^Y NL O I V I _G ^L A E N M _{G S} ^E _G ^Y N L E Y I I ^N L Q L M _G H T N N V R T _G ^N M I M F F E W D ^K H G N I K T _Q ^L M F F D W D ^E _{Q G} N K Y N I M F F D W D _G ^K

6 ^W 0 ^{5 0} _{1 7} ^{. .} _{7 5} ⁷ 2 _{3 4 5 6 7} ⁹ ₉ 7 ⁷ ₃ ⁷ ₃ ⁷ ₃ ⁷ ₁ ⁸ 3 ₃ ¹ ₈

B ₇ ⁴

VAD _G ^N TTKFFE _G ^S KRVEFKF _G ^D _Q ^R YYIKLFY KFIKVN _Q ^I VKKIKFIKVN _Q ^I VKKIKFIKVNI _S ^S V EVF ^K APFE NALFKFAKK NRA D KK ^{L Q} RTEE _S ^L A M E _S A M LVL _Q DYNE _Q ^S DLF AII ^I KVN QRTEEV ^G _G LFLPPN _S ^{D S} KK ^Q RTE PPN _S ^{D S} KK ^Q RTEKVE _G ^G GLFLLLR CA LLKP ^D R V _S ^L P ^K _G L II LFKREVL ^F _Q II _G LFL QHYILFKREVL ^F _Q II QHYILFKR PN _G ^G EFET ^{Q A} LN S _S FA ^S _{S Q} VTY ^H IALFL ^P V _G YH YI LDEK DY _G ^N TIEHLDEK _G TIEHL VLNI ^L A K ^A _S HLFKR _Q DIKK EH GKALDEK NEYK _G ^Y AHPLKANEYK ^Y DY ^N DEK ^S VI _Q ^T QRKI G AHPLKANEYKLNYE NY ^Q H ^A DIPLA Q ^S _S Y _G ^G _G KHV FPLDLVEYR ^H VKP KA G _S ^K ATE DLENIIM _S ^D DAL DLENIIM _S ^D DAL DLENII DA _{G S} NA _G KDEI _S ^K DLNTAERLIMPNDD TALK V HLA _S ^T TALK V ^K HLA _S ^T TALK ^I D G ^F T GK SDVAPV _S ^L DDKHHK T LLE IVLWV IDI ^L M SEK _G ^K A LN DI ^L M SEK _G A LN DI ^L M SEK _S ^I FK KH LKELIVI DL ^R K GIL _G ^N YEI ^L M SEKDYYKD _G ^N YEKHRVRH _S ^I EL ^N I GYEKHRVRH _S ^I EL ^N I GYEKHRKDEV GA _Q ^T LYDA TLVEKHRV EKDLNHE LNHE DEKDIDKI RHERRVI ^Y VI _S ^L VTKI GEKDDIDLFVLEDKDL ^D AFH ID SDKI ^G L GVL LPEEKY ^N VLIDEKD GEVL EKY ^N VLI GEVL NHE AEL YVWDLKRYLPEE FLFDAN _S ^{K Y} LPE DAN _S ^{K Y} LPEAKRN SFLFPIF EYT ^R VIL Q HMLTFLFD ^K HKNLRR _S ^Y GATK NVLV ^K KRR _S FLF Q KDK ^{S N Y} FL ^{G S} NF _Q MLDNVLV NF ^K KRR Q MLDNVL ^{N G} _{S G G} ^N _G ND ^D KVK SVIKIKDD RHKA ^K MLD SKDK ^{T E} KTI _S V L _S KDK KTI _S ^S V L _S ^T KDK KT ^S F G ^N _{Q S} P SNK _G FFNWH _S ^G LE IKT ^Y VLV G NHRHLKAA _S ELKVE _G ^G _S ELKVE _G ^G A _S ^E ELA _Q ^A V SIVN _S ^Q I KPY NAK _S ^{K K} TI EYPYDAK DE ^E TKAA ^E TEIFIP _G ^{L V} RR ^E V GE EPE ^S _Q LK GNTLKDILIPE _Q ^{F T} LLR _G YAK LLR ^E TKA GYAK ^F DE LPL _S ^Y LRNEEHN ^S T NITK QI ^T _{Q G} AIL ^E P _Q VI _Q ^T RPE ^F DE Q P ^{T A} _{Q Q} LV _Q ^S RKI _S KVKL _Q ^E LV ^S VI _Q ^T _Q ^E P _Q ^T QRKI ^A RPE SKVKL _Q LV ^E I GI ^N L SV VV F DT DK _G ^E _G ^{Y A} VP _Q ^F EPL QKNLILV _Q ^{S S} NLLRVKL SIK TKKPKYILNYEARKKPKYILNYEARKKPKYIVHKK RK _Q ^{V V} RK FE _S ^L _Q ^K LDNKEYDPKYILTE ^T EYDTTFD D DYDTTFD NYP ^L _G EK SLH F AI RDAANLD LR ^D _{G S} LYDAKLDE _G ^{I F} TL VDAKLDE ^I D LDYDTTFDVDLR E _G ^F T GKLVDAKLDEEITV D ^L YFK _G I _S ^E ND ^E NTA QEEEIDLKLDE _G ^I VV LNLK ^I _G KL SFKRIDLDLNLK _S ^I FKRIDLDLNLKDVT L _{G S} ^L KKKPEKFEDDILPT RK ^N H GN ^L DLD GTEE SFLPFD KRRKVYLFKV ^Y E QE ^L YLK GNIKNYKPTIKL ^K N DEVRKTEE KDEVRKTEE N LYIA L _S T ^I K SIDKI DIKL ^K N ST _S ^I IDKI L _S ^K T _S ^I N DEIL E _Q YTDFYKPDDVRLKTKIDLPLI LMEAKRN _G ^R F RNLMEAKRN ^R DIK GF NLME ^Q KF DKKK _G ^A EAKMETMTRIRALELMEA ^I RN YRNPIF F _S ^I LFYRNPIF NF ^I R SLFYRN ^D _S VH SLKK KRKIPVIEWV DNKPH HFYRNP ^I ELV SF ^S _S LF Q HYKHD F ^N N K HYKHD F ^N IFII PA ^L K _G ^W YHKN NE ^I I SEH _G ^W YKYIP _G ^{S N} _Q E F _G ^W YKYIP _G ^{S N} _Q EK YKHDHNRK F ^A LL NTL _G ^F NLF ^G _{S S} D ^R MRN G ^R IKN IKYI _S ^K _G ^S DKE I IKFFNA ^A _S PL QV A IKFFNA ^A _S PLF ^W H GYKYIP QV EA KFFN ^S DIK GIRD A _S AN Y _S ^V TKFFNAKR ^N L _S ^V AADLPL ^Y E SFA _S ^V AADLPL _S ^Y FA ^V I S FAAD QVFP ^F _S E SEL ^{Q R} ID Q _S EH ^N _{S Q} D ^E E GF PLDNTERR LLN ^A NPFAADIIF ^K _{G S} TN ^T F SD ^T S FD F ^E EL I L PN ^T F SD ^E EL ^E I L N _S D ^A D Q F _G ^E I _S ^N V _S ^L I _S ^N V ^L P S ^E EL _Q L ^R W GV I KILL V _G ^{N V} I S Y A _S ^S L _G ^T N ^E EL QAF _S ^{D N} F _Q ^K A F Q ^A N _S ^A DVHKKY ^A _G ^T F ^A _Q F _{G G} K _Q N _S ^A DVHKKY _G ^{A T} F GK ^A _Q AA QN ^A F SD ^K I I _S ^N ENKR _S ^R LRD _Q ^L Y _Q ^I LRVIE _Q ^A N DV ^A _S K _G ^T K QV ^G L GELIE ^N TKKVDVRK HKKKLH A LATEKDH T _S ^S K PL IDH _G ^L IE TKKVDLRK ^K _S DLNY ^K A L ^F M CFYVIMD Y _G ^N I ^T R Q E YV ^K EDEITVP _S DH _G ^N ITVP ^L IE SDH ^N TKK _{S G} ^E D _G ^E G EDITLT GKLKDVTLT YV ^K EDE GKLKDVTLT V _G ^K KL ITW ^L F _S K S LL ^P ENLHEIL _G ^L KV ^K ED _Q ^V GKLNI _S ^N E _S ^A T _G ^L DIEDILYIAIF _G ^L DIEDILYIAIF ^L Y GDIEDI ^I YED SMNN DIA _C ^G I _S ^F RL _G IRKKTTN VIDDILHKEA IVKN CIIE ^Q KFIT KLIVKN ^Q KFIT KLIVKKDNN FD VKNETK ^I A _S ^I ELIV DLVL ^T KL S _S ^I EK ^{I Y} LE _S VHLF _S EK _S VHLF _S ^I EK FV SK _S D ^A T SLYKA DYEK ^K N ITKLTY _G DL _S ^D LKKKLY ^Y LE GDL _S ^D LKKKLY ^Y LE IF _{G G} DL ^F _{S G} ^R RE SV ^E E GL ^E VL ^D YF ^N _Q FLAPEL ^Y I _C D GELTDVKRYP ^E L QFAEDHNRKDNP ^E L QFAEDHNRKDNP ^E L QFAED EI ⁰ NTY _S KI _Q PY ^F _{Q G} RNLLKLFADD YIVKRKLE DIKAIKLE _{G Q} ^N DD _{0 Q} ^L RDA ^S DIKAIKLE LAAHID ^L TMEIK H _G ^{E Y} FH GNY _G IRDRINTA ^Y FH GNY _G ^S IRDRINTA ^Y FH ^L GNYDLLD O N N K I _Q M K H R E ^D _{Q S} T E I K V M ^N E G A ^Y F G N Y I ^Q KI KNTA S V N _G ^R R M A F D W T A D R W I N M A F D W T A D R W I N M A F D W T D Y I K ₆ ^W

0 ^{5 0} _{1 7} ^{. .} _{7 5} ⁷ 8 _{9 0 1 2} ⁹ ₉

8 ⁷ ₃ ⁷ ₃ ⁸ ₃ ⁸ ₁

3 ¹ ₈

B ₇ ⁴

ET KK RTEE _S A KK VYNNA _G DDD KK KVYIKLFM _Q KKIKV ALNIDLH GY II _G ^Q LFLPPN ^D M S ^S I ^I K QRMKDV ^D KDYVDL KHW RTTNKA HII RT ^K N QARAA REH _G ^{W A} RYILFKREVL ^Y _Q IALFVPT ^T _G VKDNEE GKY EAN _S ^{L I} I _Q ^I SMALFKEV ^S E GNI M _G ^E LFLPV N _G ^E YETT SKEHLDEK NY ^N _Q H _S ^I GTITHLFMLNEVPK _C ^AA EFD GKVVRHT HHLLYLPV _G ^T RAL _Q ^S HLFT V _G ^T FRRLKY ARKANEYK _G ^Y HPLRALDER VWNEEPTI LD DLENIIM ^D A SDAL LNEYR ^Q I GNA PIILLK ^N HK _G ^K RALDERKEVA TKA DE ^R N Q EI GYR DLNEYE ^L KPH LVTALK MV LA ^T D STADRLEMPN _S ^I L NYILADP _S ^D TADRLE _G ^{H E} VY _Q ^K SA ^S DL _G ^L EYR _G ^Y STAERLIM ^I V _G NI ^G H L _Q R SARNK _Q DR RI LDI _S ^L EK ^K H N _G A LLE IIVLEA _S ^D ETK RK _G YEKHRVRH ^I LNT SEL YDL _S ^P MKNY ^S NIV N IMPN ^I L S L LLD MVPNP S L ^N LL GYDL _S ^L MVVLE _G ^D I _G ^N YDI _S ^L EKVL ^{T V} HDE GPIL RD LVDEKDLNHE IE ^K LKLDV _Q ^S SEETKILT _G ^V K _C ^E LIDKHEKNYN GF VL LPEEKY ^N V _Q ^G LE ^K H SK ^A V QI ^D A S F LR VLDAKKV ^S LVEKHRVNY ^K _{S G} LLIYK QVLEDKDL NF RR _S ^Y FLFDAD ^K _G EI S KRR IPDE ^{D N} ITNN VV ^S N SA KRYLPDL ^D AT _S ^{R K} _S DLNPKRYLPEE ^D AR ^I F RK SDD _S E _G ^T IL EKMLDYVLV F _Q L _S ^Y LLED ^K _{Q G} A ^G _G LKTE _G ^I G LK D FLTLLEE LF KNKEKTI ^S N SV ^T M DDKVFVRH ^K DMMLK NY ^N A GHD KDDEVFD ^K H GA ^A N GN ^S MLTFLFD GKDD ^K H FNKI GA ^L A GL EAKAA LKVE ^G L _S K G A ^T _Q FYKMK D FAAK ^S E F _G E ^E T ^K EKLI _Q LPKEEI ^L KHL A EKLVRH YKA ^D VLV GKTIRHHM ^D DT SFL _G ^{T T} LLR ^K _S TK ^N H SYVE YITA PLR _S ^K K _S ^K RAK _S ^K NH LP PE _{Q Q} VI ^T _G Y _S ^K Q RP _Q ^T E QFFNP ^I _{Q S} KLKPD ^T ETVNH ^T A QM NLKKYV KP ^S ELK GE ^T RATED S KL ^E P QLV _Q ^S RKI _S ^A KV ^I _G ELI EK ^K N _Q ^F IT ^L _G PTV RV _S ^Q _Q ^F NP ^T L Q ^E Y _Q R SDV ^{S R} NL G _Q YV Y ^A V G KKPKYILNYEARK ^D _Q DPT ^A D QNT FDDV SLLLW _Q ^S TVK _S ^A VP ^S E _S ^V GDKTV ^R V _Q D S K _S ^T LMLL ^D N SNTAPKIL I _Q ^S K DTTLD D TLDYDKKYVLTEMA _G ^N _Q ^A RALE YDKKNV _Q ^S RIKLIYDK ^I L QYIL ^S NE _G ^S SITD ^L KV SRM _S ^D P ^L Y S DAKLDE _G ^{I F} KLVDAALTI LRVLKK ^A NAT SDLIF LT DLDLNLK ^I _{G S} FKRIDLDLDE _G ^I VLIL ^K HY DAAEKILTEKMTDAALLD TEKKTLYF IF TEE ^Q _S N DD RVR SFP ^L DLDL G TKEIFE ^I L GVVIR ^T DLDLDE _G ^I LRKLLF GTH VVVEEN _Q ^K _Q ^S IT VKL ^K N ST ^I KDEVRKT SIDKI DI ^T EIFEKTKNR ^S T G ^K LDF K _G IA QLPNLKNY _G F V _Q ^S V LT IKAPNLKKKN VK _S ^{E I} NIK GL RKIFFE LF RNLMEAKRN _G ^R FVRLKTIID ^V KV Q IDD _Q ^E IPL _G ^E VI VRLKTIKNY ^T L VR KT ^I K QINYN ^Y _Q KL _S ^V LFYRNPIF LEIM ^F P _G ^R MDID ^V _G F AL ^{L KQ S} _Q LMEADF ^{L L} E _C ^L DN HHKHD ^S F ^V NFA N _Q EK HFYR ^D A QP ^I _{G S} F ^L IVK ^A ALDI S _{Q Q Q} REA ^F _Q NK QPEF ^V _{S G} E AI _G ^Y YKYIP _G PLF _G ^W YNKEN ND ^Y N _S ^Y K ^S V QI SEI _G E _G ^I IHKI ^W HFF GY ENP _S ^I F FD ^W HFYRNP GYNKTE ^F K _Q YA ^L E SK SFPKN _Q ^I HI RI IKFFNA ^A _{S Q} V ITYIA _G ^S DKML EVDDLE ^N Y GI ^N K IE D _S ^M EA IN _S ^V TFAADLPL ^Y EA SFA _S ^V TKFFEAKRVE ^F A Q IKKITT ^V I _S Y STKFFE ^S D GDKLFP ^V ITYIK _G ^S DD STKFFNADK ^Y P SL ^K DKM SIPR NN NPD L V L PNPFEADLIFKFA _G ^Y NLDDVK ^K I Q NPFE NPFEKDIKRLENFLK LA ^G E TF ^A _Q F _G ^E I _S ^N V _S ^L YNERDNF R FHWLAYIKA _S ^{T S} NAKRV QDLIFK ^L A S YL _G K _Q N _S ^A DVHKKY _G ^A _G ^T DP LA ^D I _S ^L RVEN ^T YNE GKP ^T FN EL IFVIVYVD I GE IE ^A LNF _G D ^{D D} F ^A DNE NTAKVDLRK NT _S ^Q _S ^A FI ^S _{S Q} V ^M KPDT VINL IET _S ^Q _S FA ^D RY _S ^G ID ^P _{Q Q} K ^A _{S S S} ^F V ^Q K KD DH _G EDEITVP ^L I SDH TAATPM ^T Y _G ERHT _S ^N QK IY _Q N DH ^S _S VKA DH ^A _S RK _G EF S V _G ^K KLKDVTLT Y _G ^L KEI MP ^T T S ^V L K ^A L SE ^L A ^A D VTPT GK ^I _{Q Q} PLALL ^L KK VVKL _G ^A KV E _S ^{V L} Y GDIEDILYIAIF _G ^L TL _G ^K _Q ^E DEI _S ^K DLK _S ^{N E} _Q N G _S ^T EHM _Q ^M AK ^L Y _{G G} A ^G KDEV ^L Y _{G G} ^V ED ^V _{Q Q} PLII GK ^F DPT LI LIVKN IADDK HKKK DYKITRLL ^L _G ^L NKLNI ^N KD _S ILL FN ^I K SEK LK ^Q KFMT ^I V _S DDKHI ^K FKT SD ^I V _S EDILI _S FK D _S VHLF _S ^I E IVF _S ^L DLVI ^E F GIA ED D _S ^L IEITKIPEK _S ^S IL ^N _G ^Y MN _S ELIVI K ^I L CL _S ELILKDHKD ^T NYI ATK AE Y L _G ^Y EL _S LKKKLY _S RN YDA VI ^L H SDL _G ^R KNYAA IRDDL ^Y _{C G} ILDV SKP _Q ^E FAEDHNRKDNPKV ^Y V GEKNDID YERN HMRY KVI _G ^Y EK TKDI ^Y IK ^H V DLTIT _Q ^T MKI ⁰ PN KME FH LLAELKYIW _S ^S LYT ^I D S DV KILAEL _G DID ^K AI _{G Q} ILADD IK ^K E GEKNE ₀ N ^S DIKD D NTA _G ^Y NY _G IRDRIR ^N LI V ^T KHL _S ^F K _G ^Q DK ^R R GKD FL VW ^I V Q D FH ^E D G INL KTE O K _Q M A F D W T A D R W I N M _{G G} ^{N Y} F G N D T ^Q K S V I _Q L K W D F T K K E R M _G ^N _G ^N _G ^Y N D ^Q Y G D K V V _S ^S M _G ^N _G ^N _G ^Y N Y I _Q ^Y K W L _S ^N M M L ₆ ^W

0 ^{5 0} _{1 7} ^{. .} _{7 5} ⁷ 3 _{4 5 6 7 8} ⁹ ₉ 8 ⁸ ₃ ⁸ ₃ ⁸ ₃ ⁸ ₁ ⁸ 3 ₃ ¹ ₈

B ₇ ⁴

RYWEK KF _G ^D _Q ^R YYIKLFY KFE _Q ^R YYIKLFY _Q ^I IDI _S ^L K _G ^Y P _G ^V _G ^G KFIKVN _Q ^I VKKIKF _G ^D _Q ^R YAIK PDDKE KKIKVNNRA ^G D KK KVNNRA HEKHIMPNY _S ^N KK TEE _S ^I A M KK KF KL II _G L II _Q ^I RTEEV ^G D K GL KAEAKM VLKE II ^Q R GLFLPPN _S ^{D S I} KVYNN SK _Q ^F IR ^K RTEEV GLFL V _G ^K YH IALFL V _G ^K YH L IPR _S ^V DYMI YILFKREVL ^Y _{Q Q} H ^I I _Q RMKDV SIALFVPT NRHVD ^H I SHLFKR _Q ^P DIKK _S ^H HLFKR _Q ^P DIKK _S ^E A _S ^Y FLKV APY EHLDEK Y _S ^N TITHLFMLNE N ^K YTN KALDEK KP KALDEK KP LDYVDL _G ^D DDD KANEYK ^Y D G AHPLRALDER K _S KA DLEEYR _G ^{H K} V SATE DLVEYR _G ^{H K} V SATE _G ^D YKDNEEKHW LENIIM _S ^D DAL DLNEYR ^Q I GN GM _G ^D KL TAERLIMPNDD TAERLIMPNDD AV FDEAN ^L D S TALK KLYKT LE MIVLWV LLE MIVLWV IL _C ^AA E GKVVRHT LDI ^L MV HLA _S ^T TADRLEMP SEK _G ^K A LDTLLE GKVRY ^N L GYDI _S ^L EKDYYKD _G ^N YEI _S ^L EKDYYKD KREEPTI K _G ^K _G ^N YEKHRVRH _S ^I EL ^P IIV T ^A FKR LVEKHRV FH VEKHRV FH LIILLK ^N H GY DLNHE ^G YDL _S MKN QIE H V T _Q EEK VLEDKDL ^D A SDKI ^G L G VLEDRDL ^D A SDKI ^G M G KD NYILAD ^R VDEK S ^D L S VL LPEEKY ^N V GEILE _S ^K K _Q ^A I _S ^D QYPYA KRYLPEE KNL KRYLPEE KNL RA _S ^D ETK IV RR _S ^Y FLFDAN _S ^K RR PDE NLEEF MLTFLFD ^K H GATK LTFLFD ^K H GATK KKLDV _Q ^{S S} N SVL ^E MLDYVLV NF ^K K Q ML ^Y I SLLED _G ^K EK ^L I KDD KA ^K M S KDD LVRHKA ^R K S VEETKILTDK _C KDK TI _S ^S V L _S ^T KDDKVFVR RE _Q V _S ^E KV ^Y VLVRH RHL KT ^Y V G TINHRHL L AWP ^K _G INH S ^K T YD AK _S ^{K K} LKEYPYD D ^S IMNN LR IKVE _G ^G SLKTE _G ^I VV ^S N KAA ^E K SE SA AK DE ^E T ^K A KLI ^{N S} _Q LKEYP _G Y _S ^K E S ETK _S MFY ^I I AK SY PE LI PE ^S _Q TLKDILI NDMMLKLK ^T LLR Q VI _Q ^T P _Q ^{K T} ELI EAVYA VP ^F _G NTLKDI QEPL LRVP ^F _G N QEPL LMR _Q ^Y VFYKMKNY ^N VD PE _Q ^F GHD VKL ^E P QLV _Q ^S RKV ^A R SKV ^I _G S _Q DPT ^A VKKAL KNLILV ^S NL Q _S IK LPKEEID KHL KKPKYILNYEARK _S ^D LLLW ^S _{Q Q} T VRLML YDPKYILTE ^T T KNLILV _Q ^{S S} N SIK GE YDPKYILTE ^T T D E YITA ^L PLRYDTTLD D TLDYDKKYVLT IKLNE DAANLD LY DAANLD LR ^D _G E T SLY LE _Q ^K FFNP ^I _{Q S} KLKDAKLDE _G ^{I F} KL DAALTI TRT KLDE ^I LR _S ^D GVV H DLKLDE _G ^I VV RFDDV N _Q ^F IT LDLNLK ^I _{G S} FKR _S ^V DLDLDE ^I L GV QVN ^S A DL GF T ^Y E YLKRK _G ^N N _G ^L T E YLKRK ^N H GN ^L V G AL P _G ^S DKTV ^R D S TEE PVADM V _Q E _G ^L NIKNYKPT V _Q ^Y E _G ^L NIKNYKPT H _G ^{N A} V Q NATRALE IKL ^K N ST ^I KDEVRKT EIFEKT SIDKI DI _Q ^T LPNLKN PEVFE VRLKTKIDLPLI VRLKTKIDLPLI _G ^W YKK _S ^A DLIF EAKRN _G ^R FVRLKTIID YL ^VG R ALELMEA ELV ALELMEA LV I T LDF ^K HY RNLM SN ^I LFYRNPIF ALEIM A GL _{G G} H FYRNP _S ^I F ^I I _Q ^S FYRNP ^I E SF ^S T _G ^{S K} IA ^Q FP ^L _{S G} HHKHD F ^V NF QEK FYR _Q ^D P _S MPNYM ^W H GYHKN EH ^W H GYHKN ^I I _{Q S} ^{V I} YNKEN IVLKE KYI _S ^KS NE _{S G} DKE ^S NE _S EH NPV ^K _{G G} F ^S _S P _G ^{S N} PLF ^W H G YIDD ^E V _Q V _G YKYI QIPL ^E LT ^W GVI NA ^A _{S Q} V ITYIA ^S N GD GNYII ^V I STKFFNAKR ^N I KYI _S ^K _G DKE GL ^V I STKFFNAKR ^N I ^{T K} _G L _G N IVK ^V IKFF A DLPL ^Y EA SFA _S ^V TKFFEAK V APY NPFAADIIF _S ^{K K} T NPFAADIIF _S T IK _S ^{L S} V ^{KQ S} _S TFAA D _{Q Q Q} NPD L V L PNPFEADLI L _G DNA D _Q A D HI ^Y K _Q I _{S G} E ^I _G IHKI Y F ^E E Q F _G ^E I _S ^N V _S ^L YNERDNF EKHW ^T F ^E EL ^D F LN ^T F GN ^E EL ^D F F _Q ^K AD S _S ^N Y K _Q ^A N _S ^A DVHKKY _G ^A _G ^T DP DEAD ^L _G N S IE ^A _Q AF _S ^N F S _Q N EL IE ^A _Q AF QN V ^A _{G Q} V ^G LN DDLE _G ^N I ^T GEL _G ^L E ^F AEV Q KKITT I IE TKKVDLRK NT _S ^{Q A} LA SFI _Q ^S VRHA ^S DV _Q ^A V _G ^G RI DH ^S D A ^Y I GNLDDVK _Q ^K H _G ^N DEITVP ^L I SDH TAATP INHK ^E DY G ^N T _S K G ED ^V PL QI ^{T N} T _S K ^V PL RI IV FHWLAYIKA ^T D S YV ^K E GKLKDVTLT Y _G ^L KAY D ^L Y GKV _G ^K KLNI ^N _{Q S} E ^A E _G ED _Q I ^T ST ^L Y GKV _G ^K KLNI ^N _{Q S} E ^A E TE ST YE LTD _S ^R N IDDILHKEA IDDILHKEA PE ^M KPDT VEN _G ^L DIEDILYIAIF _G ^L TL _G ^KE KEI QDEI GERHT ^N R S INL ^I KLIVKN FIT IADDK S NIA ^I V SELIV NDLVL _S ^{T I} V SELIVKNDLVL _S ^T KI EK Q _S ^S VL K I _C ^K DITKLT YEK IRDITKLT KT ^A TIY N ^Y LK ^Q K SVHLF _S ^I E IVF ^L H SD S ^V L _Q ^{V A} L _S L _S ^D KKLYD _S ^L IEI LVEK ^E YE C PEL _G ^Y ELTDVKRY PEL _G ^Y ELTDVKRY MAK _S ^N _G ^{E T} _Q NK SEHM ^M _S E Y QAKP ^E L _G D QFAED ^L K SRKDNPKV ^Y V GEKND ⁰ LR N KLFADD KRKLFADD KME H _S ^H DIKTIKLLAELKY _{0 G} ^I VV _S ^S K K E ^E YIV ^E YIVRRNF ^E FDYKITRLL YFH _G KI ^R KK E FH _G KI _G IA ED Y IPDRIR O K R K N A D M _G ^N A _G N Y I _S ^Q V N _G R M _G ^N A _G ^Y N Y I _S ^Q V N ^R KKF G R M P P E K _S ^S I L _G ^{N Y} MN NTA ^Y F GN S R N M A F D W T _S ^G D K W I N M ^{N N Y} FLI G _{G G} N D T _S ^Q

6 ^W 0 ^{5 0} _{1 7} ^{. .} _{7 5} ⁷ 9 _{0 1 2 3} ⁹ ₉ 8 ₃ ⁹ ₃ ⁹ ₃ ⁹ ₁ ⁸

3 ¹ ₈

B ₇ ⁴

L _S FKF _{G Q} YAIKL _S F F KEE E LD KF _{G Q} YYIMLFY EYL A ^K LA LA _Q KT _S LAE LE DKKK ^I KVYNNA _S ED LKHK L _G ^S VKR _S ^KL Y QAD RI KKIKV EL FT ^E LYA SEN T _G V RMKDV ^D K GVF ^R INKT LI ENKTAWPVK K II T ^K N QAHA ^G E GR LF _S ^I NN ^H GKY ^I I _{Q S} IALFVPT _G ^T KY ^N L ILKV _Q LFAN L ADTLM YIH ^{D E} R FLPV ^N YH R VPKTHLFMLNEVPK ^G _G V AE NNKKK _G ^A F G YFLLE _S ^{Y VP} K ^R _{G G} N ^S M _G L QHLFT V _G KE ^N DRL ^S _{G S} M VWNRALDER IVWN ^K E DT ^I L GKEATKA L NTE VK _{G S} D NF KALDE ^R N Q EVKP ^V _G LPVHF GRDKELK A DLNEYR _G ^Q NA ^T _Q K YLRKRRYRA L _G ^H QL HEFAL I NR N ^I P SLTADRLEMPN ^I P _S VMLDV EF DLE YR _G ^H WYDVYK SLV ^T V S K ML ^N A G T KF _G ^{D R} N ^D V E _Q YYIKLFY LK TAE _C ^E LIM ^I VPE SANY LKLL EI LEATLLE E _G T K ^V D QK _G ^F EKY _G ^K Y KK KVNNRA D EF Y ^P IIVLEA SMKNY T Y HY VEVKR II _Q ^I RTEEV ^G L F ^N LLD GYDI ^P MVPNWN NL Y _Q ^R N SEKVL DKI _S ^K A ^K L SE ^G YDL QIE H ^K L K _S ^A R _Q ^A PA _G ^D VWFE LFL ^K _G H ^A LVEKHRVDY ^Y K SE ^T YL _Q ^{E D} F ILE _S ^K K ^A V QI ^D A _S E S KAK LIVLIYEY ^{N H} IA S _S HLFKR ^P V _G Y QNIKK ^L _{S S} P VLEDKDL ^E KNE _G I GKHI ^I V Q ^N RR PDE ^D F ^N VLR F NRPIF KALDEK P Y KRYLPEE ^D AN SDK _Q ^I LILD ^KL _Q I S _S KK A ^G _{G G} ML ^Y I SLLED ^K _{Q G} A ^G _{G G} IMD V ^V KV GT KREFD DLVEYR ^{H K} VK G _S ATE K _G ^A MLTFLFD H ^K KDDKVFVRH ^K NRI DNL _Q ^S PMLAI TAERLIMPNDD PL KDD VLV ^K HT GAK _S ^{Y K} NAKINDI SLL KKE H ^T _{Q Q} L KLI ^T _Q E MIVLWV LD KA ^D KTIRHRHLLY _S ^G EPF _Q ^S YVE ^K A S ^K E S ETK ^N H _Q L SYVE ^V KT RAEYNRKV Q T FTNK ^V LL I _S ^L EKDYYKDKT AK ^K _{G S} ELKNHPYDDV ELIT DEKP _Q ^{K T} ELI P _G ^R D ETFK ^Y IPA _{Q G} ^N YE GVYYD LVEKHRV ^D AFH IF PE ^S E VKYILIYL _S ^F AVT NT ^A V ^I _{G Q} DPT ^A DEK QNT DKDL _S DKI _G ^G IT V ^F _{G Q} NP _Q ^T DLLRNRLEPL _G ^I VK _S K _S ^D LLLW _Q ^S TVK _S ^{A M} NF E VKAL VLE SEY ^R I QT ^L I QI LPEE NL K _S ^K LILI _Q ^S _S ^D NKTTDIKK WR EMAYDKKYVLTEMALLK _S ^G KYTE ^K KVI KRY QLVE MLTFLFD ^K HK GATK ^S F SL YNKKYILRI ENDEA _G ^E EK RVLDAALTI RVLVEF KL RIDLPR KDD LILDLDLDE ^I L GVLILKFA EL _Q ^K ILPA F KV ^Y VLVRHKA _S ^K DAALLD E ^D T SFYTAELVIL K _{G G} LR KNRT EIFEKTKNRR A LFYMEVI _G ^{S K} TINHRHL ^T N QL DLDLDE ^I T S YPYDIM TE NIKVV _G ^E _Q ^RL VKDNLLA GANKT E Y ^V KI _Q ^T LPNLKNY V ^L AK SP NLEEDAF ^E _S PE ^S _Q LKE F _G NTLKDILI IE ^E _S ^I _G LTKRKKPT KTP _S ^Y E _S ^{P F} _Q ^R VRLKTIID ^V K TY ^L DV L VP _Q EPL LR ^D N QI VR TKINYPII _G ^W N LD GP _G ALEIM A ^F _{Q G} P _G ^R AK ^A _S ^{I I} _G E ^E RV Q _S DIM _G ^G H KNLILV _Q ^{S S} NL SIK MEADLLV F R _Q ^D P _S F NFPL LDHEKK _G ^V YD YDPKYILTE ^T T AL ^L K Y ^A _Q L GE _{G Q} RNP E L ^S VI _S ^L AT ^I V QH Q D ^Y N SE ^W HFY GYNKEN D _S ^Y EDLN EVKFLLN N DAANLD LR _S ^D LYKE ^W HFY GYNKTA ^L F _S ^I EH ^S ITVVNI GLK PI RL _S ^K V DLK ^I KTYD KML IA ^S N GDKML LDE _G VV H E IK ^S _{S G} NEE RVE ^V ITY STKFFEAKRVE ^R KT EK GIL EELT _Q ^T NYVY T FKFNPFEADLIFKFKIT MVLWEADD V ^Y E QE ^L YLKRK _G ^N N ^L K GE ^V ITY STKFFDPDK ^N I GL ^T EFLMNN GKIFRKV GNIKNYKPTL _S ^I NKFEKDLKR _S ^K IRTKRNL DR ^{L T} YNERDNF DLF _S ^Y FKI KD KTKIDLPLIFF ELDIFF ^K T QADLNKIN SI _{S G} DP ^D R WDL EREK _G ^{I W} VRL ^{N S} H _{G S} ^F ALELMEA ^T FN V YINT _S ^{Q A} LA ^S _S I _S ^L SFI _Q V YVKH ETVK _S AAE YRNP ^I ELV SF ^S AN _G K ^D QID IK ^P _{Q Q} E ^A HF S _S ^F V ^N _S ^G LN FE _{S G} E ^L HL GFH _S ^L KMI M _Q ^T KDH ^L TAATPM _Q ^T KIRI _S ^K VHKK ^W HF GYHKN NE ^I I SEHPK DH KKV _Q ^A V R _C ^L IIATN KMP VI ^S PIK GLDILH IKYI _S ^K _G ^S DKE IDE Y ^L V G EDNPL _Q ^T NTVY ^F SDL ^L Y _{G G} TL _G ^KE KEI QDEI ^K MP SDL _G ^E EN _Q ^L AYEAVH ^R H QA _{Q S} ^V TKFFNAKR ^N LKK _G ^L E ^G KLAI ^A E ^N YP ^S _{S Q} KKK DK KKKTKE I AADIIF ^K _{G S} TEY K ^L _{S S} EDIII ^N E _S T SEA F ^N L _{S G} EK ^S D GE LVI ^I IAD SE VF ^L H SDLVI ^I TFPKNII FL _S ^I ELILKDHKTL _S ^{V P} _Q ELKEFN TKIYD ^L I S VIEITKI _G ^{E Y} _G DM NNLE ^E NPF G FD G ^A K Q ANYA _G ^S DIKDD _G ^T N ^E EL F A QAF _S ^{D N} F _Q ^K NE EA IRDDLKLTERI RIK ID ^S PKV _G ^Y EKNDID KE ELNNL N DV ^A _{S Q} V ^G L GEL ^N Y Q EKI _G ^Y DLVITKRYKYL _G ^T DKN ⁰ IW _S KLLAELKYIW ^S N STAR EEIML ^I EDYWIE _Q ^A SRP LLH T _S ^S K PL I _Q ^D I KLLADD IVRRKYNYVKL ₀ KV ^T R ^N FLI KV EI DKMEANV ^H _Q TDY _G ^N _Q ^V I ^T R Q EEK K FH ^D D G IIRKTEIKIMN O V I _Q M _{G G} ^N _G ^Y N D T _S ^Q V I ^T E Q I L P M K R P E D K ^K _G A A M K V ^K ED G K L N I _S ^N E _S ^A T M I M _G ^T _G ^N _G ^Y N Y I _Q ^Y K N K R M K V P E D H ₆ ^W

0 ^{5 0} _{1 7} ^{. .} _{7 5} ⁷ _{9 4 5 6 7 8 9 0} ^{9 9 9 9 9} ₃ ⁹ ₁ ⁸ 3 _{3 3 3 4} ^{0 1} ₈

B ₇ ⁴

LMK FYD _Q ^K LTE _Q ^L K _S ^R KI _Q ^K IE REDIVRNI _S ^L D _Q ^L KLNNTK _Q ^S MEN _Q ^E KVFE RFV DWKLD YDDL IV ^M DDIEN ^G T RLPNITLIL FHIDNNDVT SL IDLRDDAK TT ^R K QY ^G N GD R ^W _{Q S} YVK HKLK RDNL KI ^G LYDVLVNV G LAEKLRIK _S ^K WP ^G I SE T YE E _S ^D YPRY _S ^K DNKE ERLA ^L N GL N K EKDFLNA RFFV I _G ^D KPDRLIVIKEFKRF LALKTN ^I T SR ER LYK ^G RKN LTLRVK RVT ^S K _Q ^K NPE S VVVVL ^Y E SR ^R I ST ₄ LR ^G L GI KVP _G ^S _G KDH ^S K GNKRLFKE HTR ^L PREI SNNKID LLPRNNK ³ NLYN AFDKLNE LEKMVV KNVLLKP I ^R K QLIKILPPI ₃ KRIK N WL YI ^L NL STE ^/

I RTD ₂ DYND L _S ^E DK _S ^Q R D ^I KWKL QAFMK _G RYH ^H TFN _G ^P G E ^T I ELALKYI N _Q R _Q ^L KRENKDR I PY ^L EKELR _S I ^R N SYKERY M RNFF _G ^L N ^K L S Y HKAN ₃ ⁰ V _G ^T DF _Q LKYDRAF I Y ^K Y LDT Y RA ^L MDDP S TP NLMA RKR E ^N V QEK _S ^E M ^E _{G S} KI REI ^K YEL _G ^E SEERNA RE ^I F QIY ^L V GRIR S ^F DL WPA ^H I SR ^I D SMVKYDRKYKP RKK F RKKA N _S K YYIATRNYL DEDVKY RNN ^F VN S E ^A K QKL RVL ^L R ^H DK CT _S LD LA ^I NKLLE L RKL _Q ^L DLPD KYT _Q ^I LL ^K _{Q Q} D KKKYY ^S F PFRA SK ^E L _S ^K GFVLEI ^T T _S ^A KHNRYEKK L PN ^K AYHN GYKAM LYAP MI R LNIAID ^K _{G S} EK RHFLIHDYI R _S ^D KD DAID KL ^D L SF _G ^L R _G ^Q DE YYFDIL A LALALK RTKN ^E RYNN QTDLE D LE KANNTTENL _S ^L KIPHAK L _S ^L _Q ^A ETRFPI K MDKKL A _Q ^D KD V RVIAYEENKYVMAD RFKEELH E _G ^A F ^K T T _Q HDVF KAKP V _G KY ALVIKKKVNII RKYINLP _Q ^{E E} RRKWHLD ^N Y GE RHY EVP ^S TF LPLPV QHK _Q ^I VL ^K _{Q S} HE ^E DP SHLR DY ^L PPILKRWF _G NFLLNKYR Q LDLEKD V _S ^K IVEKRIYY NFPLE _S ^E A A _G ^N _C DR _Q ^Y L AKRERR ^P A QKA R EDNIIPN ^I PI SLL ^F LVR ^R Y ^S NDINHKT KNKRHVLEAT ^N R _Q EKKLDL SYD _Q ^I EMMKR ^L VRD ^N KPKT ^R _G ELKIKII AI INY FKDKDIV ^{G L} _S VEY _G K _G RIIEF KD Q MDV ^F PK EV ID _Q ^I KI LN ^P L SLR ^K LA LVYAPKK ^R M _{S Q} FFI _G ^E EDK ^E _Q DI Q _S ^K PNT N ^I L QNL HIM VRY ^D A _S ED SDF RI M TATDE N _G ^E FIY _Q ^K PVN LNI ^A T SE ^N L ^N EFKTN L KVLA ^F DNK EDKAK T AK ^K H GA ^G _G V G ^S H _S PYDI ^{G G} GH EE ^E _{G G S} IYM PTAL ^K _Q THE QKKER VKEKA _S ^V I ^P V GE KV ^T HY QE RH ^K E WL ^D T SD _C ^T FEPLKN NRRNMN NKY NFFNI NLDP _G ^L NH ^T _Q K QL LAFV VVLAND EYIEKT ^K LP SLF ALY _S ^L ERIDR EEYPTKYV _S ^T HLKK _S ^Y T VVV ^L A RLL EREL LPFLV _G R _S ^{S G} M GRRVE ^R E QI KELN ^K NEKN NE _G ^E T _G IK SH _S ^D NT ^A Y ^K YLERL _Q ^I LID GIK MDLVYKD DL EFKRR F KHTDY ^K L SL DK ^Q I GL _Q ^S RIK _S RNLI _C ^I RY RARF FI _S ^P _G ^K DT DFT TEKAKRR KKI _Q ^S NDN ^N II L _Q ^L E R YD s

PHK ^Q Y QILRVLRKP _S ^E KIIWDHK ^D I RLN ^T T GRE _Q ^E KN Q R ^S V QL _Q ^{N F} E _Q AL SFEED IEETN _C ^y

IYIRFVVIMDMDDV K _G AD LTL YRENDKKNRILA ^G F _G ^F E _G ^{I F} ANK NRE ^V EET SHVY _G ^V ELY ^Q RYN S _Q ^Q AVR ^Y I GELEY _G ^V ₄ - TDTATNY KTRK _Q KEIRDHPI LEKELW ^R TP QRY DYTKEYI R ^D KIDD ^V HEKYALKDYIA DINNERYP IKILIEE ^N I GV ₂ - P _Q REN ^F _Q ^R T N FTDLKDVN EHIRREF _S ^L VEV KPTRX L TRL ^I _Q P _G D SF NFM _S ^T _S ^I EAFAVNAY IKHLA A _S ^D F DEL ^N R SEK ^M EY - I _S ^D V DD _S ^M EYD DDNPLIEI RLE L _G ^S TER RLN T _S EL s

HLN ^D T S DKLLKV _C ^E _C ^E VV DLPMW _S ^Y E V F TAN ^I N Q DA ^{L C} N _G KRVEFVLLPD ^{S S} DT Q _G ^S _Q R AKI I _G ^L R _G ^K T E LE _Q ^{T K} EY S Y _G ^E _C ^y

VK _Q ^L HLFKFAAAIAVDAPN _G ^T IYD ^T VR STIHLAYY Y _S ^K DIRI _Q ^A KN - QRH _S TF LKLNFD DNNEN YFYLK ^D R ^L A ^W KMKTILVKK S _S V _S P _G RKN KKNE I _S ^{A S} T ^I YIMD SE I ^R KYI o

RL _G ELKr

DAN _Q VTY VLTP _Q ^{D K} KIY GAH S F _G ^L _G ^R PLAK _G ^{A C} TIK _Q DVA ^D PE SFT QYVNFDPPP ^H M ^I _S A ^E R Q _G ^K EPI P L _S ^T IVFV PL ^S HVRYFVDHH _{Q G} FNL - GYNNNIE NAE TTK E ^I NT ^K KLKKAI ^K F SDLN E ^I A G RYF ^S TT _{G G} R ^Y _Q YLMK KD GEL EA _Q ^M EN ₂ ⁶

NNL KHK KT ^T IMIWNE _Q ^I KD GTKYPTYYVNNT _G ^W Y ^T TK CKW IAI ^K _S NLN SKDL _G ^R ILLP NLFTKRPL ^E TM SATK _G ^N AD ^V KD ^E S ANINE ^D N - GY NRKYEVTKITDY _G ^N YIDFDFLV _S ^P _S ^I KKLKKV _S ^E T _S ^T NLMLM ³

L ^A DIIDIDLF S _Q RINYVWDL ^L KA I EV GH ^{Y L} TRPAIEI _Q ^L Y LYN IV ^Y ₂

K ^{L Q} _{Q S} ^F X S _{Q S} IRAIPL _G ^I EAT _Q ^K HKEA- E ^I _{G Q} ^R W _G I ^{F Q} N ^G RVKH ^{Y I} Y _G KNPDD ^H T SLMI _G ^{I N} A SR _G ANA PI YLAKKMI u

E _{C G G} F _S VIRI _C YTVETKILNAFIRKFNED ^E K SNRD _G ^N KEDKAIF STVIILE VIYTVK NED YTNPLRR _G ^E ENDYL ^KL DNF S _C ^P LA ^F ETVKVLPI T FKLE _G ^l

M ^V I KDVTAKET _G ^L D _S ^V _Q ^E _S ^K TDK - L VHNITKEVDE ^E _{G S} E _C N ^L _{G G} RPFKLHKI S ^G W QIN IL INKDL ^T _S ^S KR _{Q S} KI EDIREDRVHKA ^E LERINELL _Q ^A X A ^{Y A} _G IELDK KNIN _S DK _G ^E _{G Q} NFYNR ^F A A _S ^G TLKKFI ^A LLVKAYVE ^E E ^Y K SK ^KN - Q _S ^{s 0} GK ^E K LDNKE _S A _{i 0 G} I _S ^{T Q} D RK _Q E ^{G P} YYA _Q V VN NY ^E NTAR _S E _S ^A FINEYV _Q ^K _S FKL ^T P CRTK _S ^{N K} NEE _S RIWYI SRNP ^S A O Q M T I N _Q E E E I M D K M W E I M K D T T M H F F L N E ^T P Q L H K V F _Q L ^K E S K ^T K Q K ₍ ^H

6 ^W 0 ^{5 0} _{1 7} ^{. .} _{7 5} ⁷ 1 _{2 3 4 5} ⁹ ₉

8 ⁰ ₄ ⁰ ₄ ⁰ ₄ ⁰ ₁

4 ¹ ₈

B ₇ ⁴ EQUIVALENTS AND SCOPE

[00549] Those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, many equivalents of the embodiments described herein. The scope of the present disclosure is not intended to be limited to the above description, but rather is as set forth in the appended claims.

[00550] Articles such as“a,”“an,” and“the” may mean one or more than one unless indicated to the contrary or otherwise evident from the context. Claims or descriptions that include“or” between two or more members of a group are considered satisfied if one, more than one, or all of the group members are present, unless indicated to the contrary or otherwise evident from the context. The disclosure of a group that includes“or” between two or more group members provides embodiments in which exactly one member of the group is present, embodiments in which more than one members of the group are present, and embodiments in which all of the group members are present. For purposes of brevity those embodiments have not been individually spelled out herein, but it will be understood that each of these embodiments is provided herein and may be specifically claimed or disclaimed.

[00551] It is to be understood that the invention encompasses all variations, combinations, and permutations in which one or more limitation, element, clause, or descriptive term, from one or more of the claims or from one or more relevant portion of the description, is introduced into another claim. For example, a claim that is dependent on another claim can be modified to include one or more of the limitations found in any other claim that is dependent on the same base claim. Furthermore, where the claims recite a composition, it is to be understood that methods of making or using the composition according to any of the methods of making or using disclosed herein or according to methods known in the art, if any, are included, unless otherwise indicated or unless it would be evident to one of ordinary skill in the art that a contradiction or inconsistency would arise.

[00552] Where elements are presented as lists, e.g., in Markush group format, it is to be understood that every possible subgroup of the elements is also disclosed, and that any element or subgroup of elements can be removed from the group. It is also noted that the term“comprising” is intended to be open and permits the inclusion of additional elements or steps. It should be understood that, in general, where an embodiment, product, or method is referred to as comprising particular elements, features, or steps, embodiments, products, or methods that consist, or consist essentially of, such elements, features, or steps, are provided as well. For purposes of brevity those embodiments have not been individually spelled out herein, but it will be understood that each of these embodiments is provided herein and may be specifically claimed or disclaimed.

[00553] Where ranges are given, endpoints are included. Furthermore, it is to be understood that unless otherwise indicated or otherwise evident from the context and/or the understanding of one of ordinary skill in the art, values that are expressed as ranges can assume any specific value within the stated ranges in some embodiments, to the tenth of the unit of the lower limit of the range, unless the context clearly dictates otherwise. For purposes of brevity, the values in each range have not been individually spelled out herein, but it will be understood that each of these values is provided herein and may be specifically claimed or disclaimed. It is also to be understood that unless otherwise indicated or otherwise evident from the context and/or the understanding of one of ordinary skill in the art, values expressed as ranges can assume any subrange within the given range, wherein the endpoints of the subrange are expressed to the same degree of accuracy as the tenth of the unit of the lower limit of the range.

[00554] In addition, it is to be understood that any particular embodiment of the present invention may be explicitly excluded from any one or more of the claims. Where ranges are given, any value within the range may explicitly be excluded from any one or more of the claims. Any embodiment, element, feature, application, or aspect of the compositions and/or methods of the invention, can be excluded from any one or more claims. For purposes of brevity, all of the embodiments in which one or more elements, features, purposes, or aspects is excluded are not set forth explicitly herein.