Producing rAAV SUMMARY

The present invention generally concerns the production of life-cycle-defective Adenovirus helper viruses for producing a recombinant adeno-associated virus (rAAV), wherein the Adenovirus helper virus contains at least one mutation selected from (a) an inactivating mutation in the transcription unit coding for the L4-100K protein; (b) an inactivating mutation in the transcription unit coding for the L1 -52/55K protein; (c) an inactivating mutation in the transcription unit coding for the preterminal protein (pTP); (d) a mutation in the L4-100K protein in order to render it temperature-sensitive (ts); (e) a mutation in the hexon protein in order to render it temperature-sensitive (ts); and/or (f) a mutation in the L4-100K protein and a mutation in the hexon protein in order to render it temperature-sensitive (ts).

BACKGROUND

Adeno-associated virus (AAV) vectors have considerable potential for gene therapy due to their promising safety profile and their ability to transduce many tissues in vivo. However, production is still quite difficult and complex and scale-up of production at an industrial scale has been accomplished only to a limited degree. One reason is that AAV virus production depends on a co-infection with a helper virus to propagate and establish a productive life-cycle. Infection of cells with a replication competent helper virus, e.g. an adenovirus, for the production of recombinant AAV vectors harbors the disadvantage that rAAV stocks are contaminated with helper virus, requiring validated virus removal steps in the down-stream purification process. Using life-cycle-defective adenovirus mutants to provide the helper functions would allow for an infection-based production system for rAAV, reducing subsequent down-stream processes and therefore increasing suitability for large-scale biopharmaceutical production by enhancing safety and efficiency, as well as avoiding the production cost of plasmids otherwise required to supply helper virus functions. BRIEF DESCRIPTION OF THE INVENTION

One subject-matter of the present invention concerns a method for producing a recombinant adeno-associated virus (rAAV), said method comprising the steps of: (1 ) providing a suitable host cell containing at least one rAAV construct,

(2) infecting said host cell with a life-cycle-defective Adenovirus helper virus selected from

(a) an Adenovirus helper virus containing an inactivating mutation in the transcription unit coding for the L4-100K protein;

(b) an Adenovirus helper virus containing an inactivating mutation in the transcription unit coding for the L1 -52/55K protein;

(c) an Adenovirus helper virus containing only an inactivating N-terminal deletion in the transcription unit coding for the preterminal protein (pTP) in order to render it non-functional;

(d) an Adenovirus helper virus containing a mutation in the L4-100K protein in order to render it temperature-sensitive (ts);

(e) an Adenovirus helper virus containing a mutation in the hexon protein in order to render it temperature-sensitive; and/or

(f) an Adenovirus helper virus containing a mutation in the L4-100K protein and a mutation in the hexon protein in order to render it temperature- sensitive,

and

(3) incubating said cell until rAAV is produced The above-described steps also constitute a method for reducing or eliminating Adenoviral helper virus contamination in rAAV preparations produced by infection-based provision of Adenoviral helper functions.

An "inactivating mutation" means a mutation in the transcription unit which renders the gene or protein encoded by the gene non-functional. The mutation can be a deletion, substitution or addition of nucleotides which either destroys the expression of the gene or leads to the expression of a non-functional, i.e. inactive protein product. In particular, the L4-100K protein mutant and the ts mutants are capsid defective, i.e. no capsids can be formed; the L1 -52/55K protein mutant is packaging deficient, i.e. no encapsidation of the nucleic acid can occur, and the pTP protein mutant is replication defective, i.e. no DNA replication can occur. Consequently, such mutants are life-cycle-defective mutants of the Adenovirus helper virus, hereinafter also referred to as "life-cycle-defective Adenovirus helper virus". According to the present invention, "life-cycle-defective" generally means that new helper virus, i.e. progeny, infection competent virus can essentially not be produced in a non-complementing cell or at high temperature, i.e. in case of ts mutations, as shown below.

Preferred examples of inactivating mutations are as follows.

In a specific embodiment the mutation in the transcription unit coding for the L4- 100K protein is a deletion mutant, in particular wherein the hexon-binding element, the elF4G-binding element, the nuclear-export signal and/or the RNA-recognition motif (RRN) are rendered non-functional, preferably wherein the deletion corresponds to at least nucleotides 25200-25400 of SEQ ID NO: 46 (NCBI Ref. No. AC_000008.1 ), in particular nucleotides 25000-25600 of SEQ ID NO: 46, more in particular nucleotides 24889-25699 of SEQ ID NO: 46, or nucleotides 24773- 25887 of SEQ ID NO: 46, or nucleotides 24061 -24665 of SEQ ID NO: 46, or nucleotides 24061 -24665 plus nucleotides 24889-25699 of SEQ ID NO: 46, or nucleotides 24061 -24665 plus nucleotides 24889-25887 of SEQ ID NO: 46, especially wherein the remaining L4-100K coding sequence consists of SEQ ID NO: 1 (Fig. 3). Adenovirus serotype 5 also serves as a reference virus with respect to the nucleic acid positions for all other Adenoviruses recited herein. Corresponding nucleic acid positions of other Adenoviruses or serotypes can be identified by routine sequence alignment.

In another specific embodiment the mutation in the transcription unit coding for the L1 -52/55K protein is a deletion mutant, in particular wherein the deletion corresponds to at least nucleotides 1 1500-12000 of SEQ ID NO: 46, more in particular nucleotides 1 1050-12184 of SEQ ID NO: 46, or nucleotides 1 1050- 12297 of SEQ ID NO: 46 (Fig. 7).

In another specific embodiment the N-terminal deletion in the transcription unit coding for pTP corresponds to at least nucleotides 10100-10300 of SEQ ID NO: 46, in particular nucleotides 9904-10589 of SEQ ID NO: 46, or nucleotides 9734- 10589 of SEQ ID NO: 46, especially wherein the remaining pTP coding sequence consists of the sequence of SEQ ID NO: 3 (Fig. 1 1 ).

In another specific embodiment the mutation in the L4-100K protein is a mutation at position 25456, , in particular a TCC to CCC mutation located at positions 25456-25458 of SEQ ID NO: 46, or a TCC to CCA mutation located at positions 25456-25458 of SEQ ID NO: 46, or a TCC to CCG mutation located at positions 25456-25458 of SEQ ID NO: 46, or a TCC to CCT mutation located at positions 25456-25458 of SEQ ID NO: 46, preferably a TCC to CCC mutation located at positions 25456-25458 of SEQ ID NO: 46. In another specific embodiment the mutation in the hexon protein is a point mutation at positions 21 171 -21 172, in particular a GGC to GAT mutation located at positions 21 170-21 172 of SEQ ID NO: 46, or a GGC to GAC mutation located at positions 21 170-21 172 of SEQ ID NO: 46, preferably a GGC to GAT mutation located at positions 21 170-21 172 of SEQ ID NO: 46.

The rAAV construct preferably comprises

(a) a construct expressing at least one AAV Rep protein and at least one AAV Cap protein and a construct containing a pair of ITR sequences flanking (i) a heterologous nucleic acid coding for a nucleic acid of interest, or (ii) a unique cloning site for cloning a heterologous nucleic acid coding for a nucleic acid of interest,

(b) a construct expressing at least one AAV Rep protein, a construct expressing at least one AAV Cap protein and a construct containing a pair of ITR sequences flanking (i) a heterologous nucleic acid coding for a nucleic acid of interest, or (ii) a unique cloning site for cloning a heterologous nucleic acid coding for a nucleic acid of interest, or

(c) a construct expressing at least one AAV Rep protein, at least one AAV Cap protein and containing a pair of ITR sequences flanking (i) a heterologous nucleic acid coding for a nucleic acid of interest, or (ii) a unique cloning site for cloning a heterologous nucleic acid coding for a nucleic acid of interest.

Generally it is preferred that the life-cycle-defective Adenovirus helper virus codes for a functional viral associated (VA) RNA I and II, a functional E2A protein and a functional E4ORF6/7 protein, and optionally also for a functional E1A protein and/or a functional E1 B protein, in particular a functional E1 B 55K protein.

Generally, the Adenovirus helper virus is selected or derived from a serotype of subgroup A, B, C, D, E, F and/or G, in particular the Adenovirus is selected or derived from at least one of adenovirus type 1 to 57, preferably the Adenovirus is selected or derived from Adenovirus type 2 (Ad2) or Adenovirus type 5 (Ad5), more preferably from human Ad2 (hAd2) or human Ad5 (hAd5). As noted above, Adenovirus type 5 serves as a reference Adenovirus for the sequences recited herein. Starting from this reference Adenovirus, engineered mutations can be made in other Adenoviruses by sequence alignments.

Preferably the suitable host cell is infected with the life-cycle-defective Adenovirus helper virus at a multiplicity of infection (MOI) of at least 1 , preferably at least 10, more preferably at least 100, even more preferably at least 500, and most preferably at least 1000. For example, a MOI of 500 worked well. Generally, the at least one AAV Rep protein is selected from Rep protein 40 (Rep40), Rep protein 52 (Rep52), Rep protein 68 (Rep68) and/or Rep protein 78 (Rep78) and/or the at least one AAV Cap protein is selected from the VP1 , VP2 and/or VP3 capsid proteins, the AAV Cap protein is derived from at least one serotype of a dependoparvovirus, in particular from at least one of the serotypes AAV1 , AAV2, AAV3, AAV3A, AAV3B, AAV4, AAV5, AAV6, AAV7, AAV8, AAV9, AAV10, AAV1 1 , AAV12, AAV13, AAV-Go1 , AAVS3, AAV-LK03 avian AAV, bat AAV, bovine AAV, Californian sea lion AAV, canine AAV, caprine AAV, equine AAV, mAAV-EVE, mouse AAV1 , ovine AAV, porcine AAV po1 -6, rat AAV1 , ancestral AAVs, natural AAV isolates from human or animals, barbarie duck parvovirus, bearded dragon parvovirus, corn snake parvovirus, duck parvovirus, goose parvovirus, hamster parvovirus, Muscovy duck parvovirus, pig-tailed macaques parvovirus, pygmy chameleon parvovirus, Raccoon parvovirus, rhesus macaque parvoviruses, or capsid variants or hybrids thereof, and/or the nucleic acid of interest is selected from a nucleic acid coding for an enzyme, a metabolic protein, a signaling protein, an antibody, an antibody fragment, an antibody-like protein, an antigen, or an RNA such as an miRNA, siRNA or snRNA.

Advantageously, the host cell is incubated in a serum-free medium.

The produced rAAV can further be purified, in particular by means of at least one CsCI gradient centrifugation, at least one filtration step, at least one ion exchange chromatography, at least one size exclusion chromatography, at least one affinity chromatography, at least one hydrophobic interaction chromatography or combinations thereof, and/or further concentrated, preferably by means of ultrafiltration.

In addition, the produced rAAV can further be formulated with one or more pharmaceutically acceptable excipients into a pharmaceutical preparation.

Generally, the at least one rAAV construct can be either episomally maintained in the host cell, or chromosomal ly integrated in the host cell.

The host cell can be selected from a BHK cell, a COS cell, a Vero cell, a EB66 cell, a Hela cell, a A549 cell, a SF9 cell, a SF plus cell, a Hi5 cell or a S2 cell.

In case, wherein the host cell already codes for a functional Adenovirus E1A protein and a functional Adenovirus E1 B protein or a functional Adenovirus E1 B 55K protein, the host cell is preferably selected from a HEK293 cell, a HEK293T cell, a HEK293EBNA cell, a C139 cell, a CAP cell, a CAPT cell, a PERC6 cell or a AGE1 cell. In case the life-cycle-defective Adenovirus helper virus contains a ts mutation selected from a temperature-sensitive (ts) point mutation in the L4-100K protein or a temperature-sensitive point mutation in the hexon protein, the cell is advantageously incubated at a temperature > 39 °C.

In case the life-cycle-defective Adenovirus helper virus contains a ts mutation selected from a ts point mutation in the L4-100K protein and also a ts point mutation in the hexon protein, the cell is advantageously incubated at a temperature > 37 °C.

An advantage of the above-described method is that the generation of progeny Adenovirus (AdV) is reduced or even eliminated, and/or the produced rAAV is substantially free of Adenovirus. As a result, rAAV preparations may advantageously be produced in which are substantially free, or have low levels, of contaminating Adenovirus. Absence of progeny Adenovirus generation can be shown by infection of the respective complementing cell (e.g. pTP cell line infected with rAAV produced with pTP Adenovirus mutant) or a cell at the permissive temperature for the respective ts mutant with at least 3 repeated rounds of infections. If progeny tsAdV/AdV mutant is produced during rAAV manufacturing, it will be detected by e.g. qPCR on AdV-specific sequences etc.

A further embodiment of the present invention is a rAAV produced according to a method as described herein.

Generally, as described above, said life-cycle-defective Adenovirus helper virus can be used for producing rAAV.

Another subject-matter of the present invention concerns a life-cycle-defective Adenovirus helper vector construct containing a mutation selected from

(a) a deletion mutant in the transcription unit coding for the L4-100K protein, wherein the deletion corresponds to nucleotides 25200-25400 of SEQ ID NO: 46, in particular nucleotides 25000-25600 of SEQ ID NO: 46, more in particular nucleotides 24889-25699 of SEQ ID NO: 46, or nucleotides 24773- 25887 of SEQ ID NO: 46, or nucleotides 24061 -24665 of SEQ ID NO: 46, or nucleotides 24061 -24665 plus nucleotides 24889-25699 of SEQ ID NO: 46, or nucleotides 24061 -24665 plus nucleotides 24889-25887 of SEQ ID NO: 46, especially wherein the remaining L4-100K coding sequence consists of SEQ ID NO: 1 ;

(b) a deletion mutant in the transcription unit coding for the L1 -52/55K protein, wherein the deletion corresponds to nucleotides 1 1500-12000 of SEQ ID NO: 46, more in particular nucleotides 1 1050-12184 of SEQ ID NO: 46, or nucleotides 1 1050-12297 of SEQ ID NO: 46, especially wherein the remaining L1 -52/55K coding sequence consists of the sequence of SEQ ID NO: 2;

(c) a deletion mutant in the transcription unit coding for pTP , wherein the deletion corresponds to nucleotides 10100-10300 of SEQ ID NO: 46, in particular nucleotides 9904-10589 of SEQ ID NO: 46, or nucleotides 9734-10589 of SEQ ID NO: 46, especially wherein the remaining pTP coding sequence consists of the sequence of SEQ ID NO: 3; and/or

(d) a ts mutation in the L4-100K protein and a ts mutation in the hexon protein, wherein

(i) the ts mutation in the L4-100K protein is a TCC to CCC mutation located at positions 25456-25458 of SEQ ID NO: 46, or a TCC to CCA mutation located at positions 25456-25458 of SEQ ID NO: 46, or a TCC to CCG mutation located at positions 25456-25458 of SEQ ID NO: 46, or a TCC to CCT mutation located at positions 25456-25458 of SEQ ID NO: 46, preferably a TCC to CCC mutation located at positions 25456-25458 of

SEQ ID NO: 46; and

(ii) the ts mutation in the hexon protein is a GGC to GAT mutation located at positions 21 170-21 172 of SEQ ID NO: 46, or a GGC to GAC mutation located at positions 21 170-21 172 of SEQ ID NO: 46, preferably a GGC to GAT mutation located at positions 21 170-21 172 of SEQ ID NO: 46.

Generally, it is preferred that the helper vector construct codes for a functional viral associated (VA) RNA I and II, a functional E2A protein and a functional E4ORF6/7 protein, and optionally further for a functional E1A protein and/or a functional E1 B protein, in particular a functional E1 B 55K protein.

Generally, the Adenovirus is selected from a serotype of subgroup A, B, C, D, E, F and/or G, in particular the Adenovirus is selected from at least one of adenovirus type 1 to 57, preferably the Adenovirus is selected from Adenovirus type 2 (Ad5) or Adenovirus type 5 (Ad5), more preferably from human Ad2 (hAd2) or human Ad5 (hAd5). Another subject-matter of the present invention concerns a method for making the above-described life-cycle-defective Adenovirus helper vector construct, wherein said method comprises the steps:

(a) deleting nucleotides corresponding to nucleotides 25200-25400 of SEQ ID NO: 46, in particular nucleotides 25000-25600 of SEQ ID NO: 46, more in particular nucleotides 24889-25699 of SEQ ID NO: 46, or nucleotides 24773- 25887 of SEQ ID NO: 46, or nucleotides 24061 -24665 of SEQ ID NO: 46, or nucleotides 24061 -24665 plus nucleotides 24889-25699 of SEQ ID NO: 46, or nucleotides 24061 -24665 plus nucleotides 24889-25887 of SEQ ID NO: 46 in the transcription unit coding for the L4-100K protein;

(b) deleting nucleotides corresponding to nucleotides 1 1500-12000 of SEQ ID NO: 46, more in particular nucleotides 1 1050-12184 of SEQ ID NO: 46, or nucleotides 1 1050-12297 of SEQ ID NO: 46 in the transcription unit coding for the L1 -52/55K protein;

(c) deleting nucleotides corresponding to nucleotides 10100-10300 of SEQ ID NO: 46, in particular nucleotides 9904-10589 of SEQ ID NO: 46, or nucleotides 9734-10589 of SEQ ID NO: 46 in the transcription unit coding for pTP; and/or

(d) preparing ts point mutations in the L4-100K protein and in the hexon protein, wherein

(i) the ts mutation in the L4-100K protein is a TCC to CCC mutation located at positions 25456-25458 of SEQ ID NO: 46, or a TCC to CCA mutation located at positions 25456-25458 of SEQ ID NO: 46, or a TCC to CCG mutation located at positions 25456-25458 of SEQ ID NO: 46, or a TCC to CCT mutation located at positions 25456-25458 of SEQ ID NO: 46, preferably a TCC to CCC mutation located at positions 25456-25458 of SEQ ID NO: 46; and

(ii) the ts mutation in the hexon protein is a GGC to GAT mutation located at positions 21 170-21 172 of SEQ ID NO: 46, or a GGC to GAC mutation located at positions 21 170-21 172 of SEQ ID NO: 46, preferably a GGC to GAT mutation located at positions 21 170-21 172 of SEQ ID NO: 46.

Another subject-matter of the present invention concerns a method for producing a life-cycle-defective Adenovirus helper virus, said method comprising introducing a life-cycle-defective Adenovirus helper vector construct as described or made as described above into a suitable host cell, and incubating the cell until the life-cycle- defective Adenovirus helper virus is produced, wherein the suitable host cell is a cell containing at least one Adenovirus complementing gene, in particular an Adenovirus L4-100K complementing cell, an Adenovirus L1 -52/55K complementing cell and/or an Adenovirus pTP complementing cell, and optionally further an Adenovirus E1 A and/or E1 B complementing cell.

Generally, the host cell is transiently transfected with or has stably integrated at least one Adenovirus complementing gene, in particular an Adenovirus L4-100K complementing gene, an Adenovirus L1 -52/55K complementing gene and/or an Adenovirus pTP complementing gene, and optionally further an Adenovirus E1A and/or E1 B complementing gene. Advantageously, the Adenovirus complementing cell (host cell) expresses the Adenovirus L4-100K protein, the Adenovirus L1 -52/55K protein and/or Adenovirus pTP.

Generally, the L4-100K protein and/or pTP can be expressed under the control of a constitutive promoter, preferably under the control of a CMV promoter. However it is preferred that the L4-100K protein, the L1 -52/55K protein and/or pTP are expressed under the control of an inducible promotor, preferably under the control of a tetracycline-inducible promoter.

Advantageously, the host cell is incubated in a serum-free medium. For example, the host cell is incubated at least transiently in the presence of a suitable inducer, preferably tetracycline or doxycycline, e.g. in case the expression is under the control of a tetracycline-inducible promoter.

The host cell can be incubated at a temperature below 37°C, in particular between 28°C and 36°C, preferably between 30°C and 34°C, more preferably at about 32°C.

The produced life-cycle-defective Adenovirus helper virus can further be harvested and optionally further purified, in particular by means of at least one CsCI gradient centrifugation, at least one filtration, at least one ion exchange chromatography, at least one size exclusion chromatography, at least one affinity chromatography, at least one hydrophobic interaction chromatography or combinations thereof, and/or further concentrated, preferably by means of ultrafiltration.

According to the present invention the produced life-cycle-defective Adenovirus helper virus has advantageously a titer of at least 1 x 10E5 i.u./ L, preferably 1 x 10E7 i.u./ L, more preferably 1 x 10E9 i.u./ L, and most preferably at least 1 x 10E10 i.u./ L, or alternatively between 10E6 and 10E1 1 particles/ L, in particular between 10E8 and 10E10 particles/ L.

Generally, as described above, the life-cycle-defective Adenovirus helper vector construct can be used for producing a life-cycle-defective Adenovirus helper virus.

Therefore, a further embodiment of the present invention is an Adenovirus helper virus produced according to a method as described herein, and/or with the features as described herein.

Another subject-matter of the present invention concerns a complementing cell for producing a life-cycle-defective Adenovirus helper virus, wherein the virus contains a deletion in the transcription unit coding for the L4-100K protein, wherein the deletion corresponds to at least nucleotides 25200-25400 of SEQ ID NO: 46, in particular nucleotides 25000-25600 of SEQ ID NO: 46, more in particular nucleotides 24889-25699 of SEQ ID NO: 46, or nucleotides 24773-25887 of SEQ ID NO: 46, or nucleotides 24061 -24665 of SEQ ID NO: 46, or nucleotides 24061 - 24665 plus nucleotides 24889-25699 of SEQ ID NO: 46, or nucleotides 24061 - 24665 plus nucleotides 24889-25887 of SEQ ID NO: 46, and/or wherein the complementing cell is transiently transfected with or has stably integrated a nucleic acid comprising the sequence of SEQ ID NO: 1 .

A further subject-matter of the present invention concerns a complementing cell for producing a life-cycle-defective Adenovirus helper virus containing a deletion in the transcription unit coding for the L1 -52/55K protein, wherein the deletion corresponds to at least nucleotides 1 1500-12000 of SEQ ID NO: 46, more in particular nucleotides 1 1050-12184 of SEQ ID NO: 46, or nucleotides 1 1050- 12297 of SEQ ID NO: 46, and/or wherein the complementing cell is transiently transfected with or has stably integrated a nucleic acid comprising the sequence of SEQ ID NO: 2, optionally under the control of an inducible promotor, preferably under a tetracycline-inducible promoter.

An additional subject-matter of the present invention concerns a complementing cell for producing a life-cycle-defective Adenovirus helper virus containing a N- terminal deletion in the transcription unit coding for pTP, wherein the deletion corresponds to at least nucleotides 10100-10300 of SEQ ID NO: 46, in particular nucleotides 9904-10589 of SEQ ID NO: 46, or nucleotides 9734-10589 of SEQ ID NO: 46, and/or wherein the complementing cell is transiently transfected with or has stably integrated a nucleic acid comprising the sequence of SEQ ID NO: 3, optionally under the control of an inducible promoter, such as a tetracycline- inducible promoter, or a promotor which drives less strong expression relative to the cytomegalovirus (CMV) promoter, preferably the human phosphoglycerate kinase (hPGK) promoter.

A suitable complementing cell can be selected from a HEK293 cell, a HEK293T cell, a HEK293EBNA cell, a HeLa cell, a A549 cell, a EB66 cell, a PerC6 cell, or a CAP cell. Generally, the complementing cell as described above can be used for producing a life-cycle-defective Adenovirus helper virus selected from

(a) an Adenovirus helper virus containing an inactivating mutation in the transcription unit coding for the L4-100K protein;

(b) an Adenovirus helper virus containing an inactivating mutation in the transcription unit coding for the L1 -52/55K protein; (c) an Adenovirus helper virus containing an inactivating N-terminal deletion in the transcription unit coding for the preterminal protein (pTP), wherein said transcription unit contains no C-terminal deletion.

ADVANTAGES OF THE INVENTION The above-described life-cycle-defective Adenovirus helper viruses were successfully designed and produced to contain as much sequence deletions as possible in the L4-100K protein, the L1 -52/55K protein or the preterminal protein pTP while ensuring the necessary functionality of the other partially overlapping Adenovirus helper genes which are required for efficient rAAV manufacturing. In addition, as also experimentally shown, essentially no generation of wildtype Adenovirus revertants were obtained via recombination between the Adenovirus mutant genomes and the complementing L4-100K, L1 -52/55K and pTP gene sequences of the complementing cell lines.

The life-cycle-defective Adenovirus helper viruses could also be obtained in sufficient amounts for the production of rAAV. In the case of the pTP replication- life-cycle-defective mutant of the present invention it is particularly surprising that, while only having a 685 bp N-terminal deletion, it surprisingly supports rAAV manufacturing with an efficiency which is comparable to wildtype Adenovirus. Furthermore, despite a small deletion in the pTP transcription unit, no revertants were generated via recombination between the Adenovirus mutant genome and the complementing gene sequence of the complementing cell line.

It was also surprisingly and advantageously found that an Adenovirus helper virus containing a temperature-sensitive (ts) mutation in the L4-100K protein as well as a ts mutation in the hexon protein was non-permissive for packaging at 37°C. DESCRIPTION OF THE FIGURES

Figure 1 shows the region of the L4-100K in the Adenovirus genome.

Figure 2 shows overlapping sequences between the complementing plasmid pBSK-CMV-TPLIN-100K and the Ad5A100K mutant (L4-100K). The numbering at the upper part of the figure corresponds to the bacmid sequence BacAd5Delta100K (SEQ ID NO: 7) and the numbering at the lower part of the figure corresponds to the sequence of the construct pBSK-CMV-TPLIN-100K (SEQ ID NO: 6). Figure 3 shows the remaining coding sequence (1613 bp) of the L4-100K protein mutant at position nucleotides 24061 ...24888, 25700...26484 according to NCBI Ref. No. AC_000008.1 . Deletion inserted from position 24889-25699, position marked by two flanking nucleotides each, black bold, inserted deletion between C|T marked by underlining.

Figure 4 shows the results that the Ad5A100K deletion mutant provides helper functions for rAAV production.

Figure 5 shows additional results that Ad5A100K deletion mutant provides helper functions for rAAV production.

Figure 6 shows the region of the L1 52/55K protein in the Adenovirus genome.

Figure 7 shows the remaining coding sequence (1 13 bp) of the 52/55K protein mutant at position nucleotides 12185...12297 according to NCBI Ref. No. AC_000008.1 .

Figure 8 A shows a cDNA analysis of the 52/55K gene on a agarose gel.

Figure 8 B shows a Western blot analysis of the 52/55K protein.

Figure 9 shows a Western blot analysis of gene expression of stably integrated inducible TetON 52/55K vector (= pTRE-Tight-BI-AcGFP1 - 52/55K).

Figure 10 shows the region of the pTP in the Adenovirus genome.

Figure 1 1 shows the remaining sequence (1309 bp plus 9 bp) of the pTP protein mutant at position nucleotides join (8583...9903, 141 1 1 ...141 19) according to NCBI Ref. No. AC_000008.1 (complement strand); transcript is getting spliced (non-coding sequence marked in grey), remaining coding sequence for pTP marked in black bold and underlined).

Figure 12 shows the results that the Ad5ApTP deletion mutant provides helper functions for rAAV production.

Figure 13 shows additional results that the Ad5ApTP deletion mutant provides helper functions for rAAV production.

Figure 14 shows the results of a co-transfection experiment of three plasmids each encoding rAAV vector, rep and cap.

Figure 15 shows the results of a single "All-in-One" transfection experiment with one plasmid encoding rAAV vector plus rep plus cap. DESCRIPTION OF THE SEQUENCES

SEQ ID NO: 1 nucleic acid encoding the L4-100K mutant

SEQ ID NO: 2 nucleic acid encoding the L1 -52/55K mutant

SEQ ID NO: 3 nucleic acid encoding the pTP mutant

SEQ ID NO: 4 sequence pBELO66 Ad5 wt (42148 bp)

SEQ ID NO: 5 sequence pGS66 (35789 bp)

SEQ ID NO: 6 sequence pBSK-CMV-TPLIn-100K (6690 bp)

SEQ ID NO: 7 bacmid sequence Ad5A100K (41337 bp)

SEQ ID NO: 8 sequence of the L4-100K deletion

SSEEQQ IIDD NNOO:: 99 primer sequence for the RED^/ET ^® recombination (L4-100K)

SEQ ID NO: 10 rimer sequence for the RED ^® /ET ^® recombination (L4-100K)

SEQ ID NO: 1 1

SEQ ID NO: 12

SEQ ID NO: 13

SEQ ID NO: 14

SEQ ID NO: 15

SEQ ID NO: 16

SEQ ID NO: 17

SEQ ID NO: 18

SEQ ID NO: 19 ) ^® /ET ^®

SEQ ID NO: 20 ) ^® /ET ^®

SEQ ID NO: 22

SEQ ID NO: 23

SEQ ID NO: 24

SEQ ID NO: 25

SEQ ID NO: 26

SEQ ID NO: 27 ) ^® /ET ^®

SEQ ID NO: 28 ®ii--r® SEQ ID NO: 29 primer sequence for the RED ^® /ET ^® recombination (ΔρΤΡ)

SEQ ID NO: 30 forward amplification primer with Kozak sequence (ΔρΤΡ)

SEQ ID NO: 31 reverse amplification primer (ΔρΤΡ)

SEQ ID NO: 32 amplification forward primer (ΔρΤΡ)

SEQ ID NO: 33 amplification reverse primer (ΔρΤΡ)

SEQ ID NO: 34 amplification forward primer (ΔρΤΡ)

SEQ ID NO: 35 amplification reverse primer (ΔρΤΡ)

SEQ ID NO: 36 amplification forward primer (ΔρΤΡ)

SEQ ID NO: 37 amplification reverse primer (ΔρΤΡ)

SEQ ID NO: 38 primer sequence for the RED ^® /ET ^® recombination (ts100K)

SEQ ID NO: 39 primer sequence for the RED ^® /ET ^® recombination (ts100K)

SEQ ID NO: 40 primer sequence for the RED ^® /ET ^® recombination (ts100K)

SEQ ID NO: 41 primer sequence for the RED ^® /ET ^® recombination (double ts)

SEQ ID NO: 42 primer sequence for the RED ^® /ET ^® recombination (double ts) SEQ ID NO: 43 primer sequence for the RED ^® /ET ^® recombination (double ts)

SEQ ID NO: 44 amplification forward primer (double ts)

SEQ ID NO: 45 amplification reverse primer (double ts)

SEQ ID NO: 46 human Adenovirus 5 genome according to NCBI database reference AC000008.1 (coding sequence nt 24061 -26484)

SEQ ID NO: 47 nucleic acid encoding the L4-100K protein

SEQ ID NO: 48 nucleic acid encoding the 52/55K protein

SEQ ID NO: 49 nucleic acid encoding the pTP protein

DETAILED DESCRIPTION OF THE INVENTION

A. Replication-deficient Ad 5 mutant deleted in L4-100K protein

I. Generation of Adenovirus 5 Deletion Mutant Δ100Κ on DNA Level

/.1 Rationale Ad 5 Δ 700K deletion mutant

The L4-100K is a multifunctional protein, which is expressed late during the adenovirus life cycle. When viral DNA replication has begun and all late mRNA transcripts have been synthesized, cellular mRNA translation is blocked by inhibition of mRNA export from the nucleus to the cytoplasm. In counterpart, the export of viral mRNA from the nucleus is facilitated and preferentially translated leading to synthesis of structural polypeptides. One responsible protein is the 100K protein. It dephosphorylates elF4E, which is a translation initiation factor. By dephosphorylation cap-dependent translation of cellular mRNA is reduced. Furthermore, binding of elF4E to viral mRNA is enhanced and translation of viral mRNAs is stimulated by ribosome shunting. Additional to having an impact on viral protein synthesis, 100K plays an essential role in the assembly of hexon monomers to trimeric hexon capsomers. It acts both as a chaperone, facilitating folding of hexon proteins, and as a scaffold promoting assembly of trimers. In case of a deletion of 100K, the AdV life-cycle is interrupted in a late phase of the infectious cycle, similar to the 52/55K-mutant. Yet, in this case, adenoviral DNA is replicated but viral particles should not be assembled. Furthermore, no inhibition of cellular RNA translation should take place, probably positively influencing yield during rAAV production. Therefore, one objective of the present invention is to delete essential functional elements of the 100K, such as the hexon-binding element, elF4G-binding element, the nuclear-export signal and/or the RNA- recognition motif (RRN), to prevent hexon trimerization and inhibition of cellular RNA translation (Figure 1 ).

Exemplarily, the N-terminal 810 bp within the 100K encoding sequence of 2424 bp length, representing nearly the entire E2A late intron, were deleted from position nt 24889 - nt 25699 according to the NCBI database reference AC_000008.1 of the human Adenovirus 5 complete genome (coding sequence nt 24061 - nt 26484; SEQ ID NO: 46). This deletion preserved essential coding sequences on the complementary strand, resulting in some sequence overlap between the virus mutant and the 100K encoding sequence to be provided in a complementing cell line. (Figure 2).

Table 1

L4-100K deletion in the human Adenovirus 5 NCBI AC_000008.1 complete genome:

...TCGAGGTCACCCACTTTGCCTACCCGGCACTTAACCTACCCCCCAAGGTC_[Ant24 889-

-nt25699] TTGCCTACCACTCTGACATAATGGAAGACGTGAGCGGTGACGGTCTACTG... (SEQ ID NO: 8) I.2 Cloning of Ad 5 A100K

The adenovirus deletion mutant Δ100Κ was generated using Homologous Recombination Gene Bridges Counter Selection Bac Modification Kit by RED ^® /ET ^® Recombination according to manufacturer's instructions. The template DNA for insertion of the deletion defect was a pBELO66, a bacmid containing the adenovirus type 5 wildtype genome. Bacteria used for bacmid modifications were E.coli DHI OBeta. Deletion region within the bacmid was located from nt 24449 to nt 25259 of pBELO66 (SEQ ID NO: 4) which corresponds to nt 24889-25699 of human Adenovirus 5 (NCBI AC_000008.1 ; SEQ ID NO: 46).

For the first and second RED ^® /ET ^® recombination step following primers were designed:

Table 2

Ad5 mutant 100K (intermediate): 50 bp (24838-24888) 100K left of deletion + 24 bp rpSLneo for integration into rpSLneo cassette:

TCGAGGTCACCCACTTTGCCTACCCGGCACTTAACCTACCCCCCAAGGTCGGCCrGGrGA rGArGGCGGGArCG

(SEQ ID NO: 9)

Ad5 mutant 100K (intermediate): 50 bp (25700-25749) 100K left of deletion + 24 bp rpSLneo for integration into rpSLneo cassette:

CAGTAGACCGTCACCGCTCACGTCTTCCATTATGTCAGAGTGGTAGGCAArCAGA¾GAA CrCGrCAAGAAGGCG (SEQ ID NO: 10)

M3: Ad5 mutant 100K, deletion No. 24889-25699:

TCGAGGTCACCCACTTTGCCTACCCGGCACTTAACCTACCCCCCAAGGTCTTGCCTACCA CTCTGACATAATG GAAGACGTGAGCGGTGACGGTCTACTG

(SEQ ID NO: 11)

Bacterial amplification of accomplished bacmid was done in DHI OBeta and purified via Qiagen Large Construct Bacmid Preparation Kit according to manufacturer's protocol including the deviation that no exonuclease digestion was performed.

II. Cloning of plasmid DNA encoding Ad5 "L4-100K" for the complementing cell line

To produce life-cycle-defective Adenovirus mutants that carry a deletion in a crucial gene during life-cycle as virus particles, a complementing cell line expressing that deleted gene is necessary to get virus amplification and progeny. These produced virus particles are then life-cycle-defective on non-complementing cell lines. 11.1 Amplification of the target gene "L4-100K" as insert for the complementing plasmid

The complementing gene for the Adenovirus deletion mutant Δ100Κ was extracted from the bacmid pGS66 encoding the Ad5 genome sequence w/o E1 via Polymerase-Chain-Reaction (PCR) using primers additionally encoding endonuclease-restriction sites Not! and Sma\ for further cloning steps. The forward primer additionally encoded for a Kozak sequence which was planned to be inserted in front of the 100K coding sequence.

Table 3

Ad5 100K Not\ Kozak forward

tGCGGCCGCgaccATGGAGTCAGTCGAGAAGAA (SEQ ID NO: 12)

Ad5 100K Sma\ reverse

attCCCGGGCTACGGTTGGGTCGGCGAA (SEQ ID NO: 13) The amplified fragment was digested with Not\ and Sma\. This fragment represented the insert encoding 100K (Figure 1 ; SEQ ID NO: 3) to be introduced into intermediate cloning vectors for subsequent bacterial amplification and introduction of the complementing gene into cells.

11.2 Preparation of final complementing plasmid "pBSK-CMV-TPLIn-100K" The generated PCR fragment (2424 bp) encoding the 100K produced in 11.1 was introduced into the backbone vector pBSK-CMV-TPLIn (4248 bp), containing CMV promoter and a tripartite leader (TPL) sequence flanked by an intron, which had been prepared previously.

11.3 Analysis of cloned "pBSK-CMV-TPLIn-100K"

Successfully cloned "pBSK-CMV-TPLIn-100K" was amplified in E. coli XL-2 Blue to obtain material sufficient both for characterization and stable transfection. Transient transfection was performed to analyze expression of 100K via Western blotting. Therefore, 1 E6 HeLa cells were seeded on 6 cm dishes and transfected 24 h post seeding under following conditions: transfection reactions of 250 μΙ NaCI containing either 5 g DNA or 60 μΙ 7.5 mM PEI were prepared, mixed, incubated for 10 - 15 min at room temperature and transferred onto the cells after medium change. Cells were harvested 48 h post transfection and processed for Western blot analysis. 50 g protein were loaded on 8 % SDS-Tris gels for electrophoresis in Tris-Glycin buffer. Transfer was performed via tank blotting on nitrocellulose 0.45 μιτι membrane in Towbin buffer containing 20% methanol. Subsequently, membranes were blocked in 5% milk powder in 0,1 % Tween-TBS over night at 4°C. Afterwards, membranes were incubated for 2 h with 1 antibody 100K rabbit 2a #136 - 148 diluted 1 :100 in said blocking buffer. After three rounds of washing, membranes were treated at room temperature for 1 h with 2 ^nd antibody Anti-Rabbit IgG-Peroxidase Antibody produced in goat (Sigma) diluted 1 :20000 in 0,1 % Tween-TBS. Detection was done at AGFA CP 1000 via Pierce West Pico Chemoluminescence Substrate using GE Healthcare Amersham Hyperfilms.

III. Generation of complementing cell Line for Δ100Κ Mutant Virus production

///.1 Generation and selection of stable cell clones expressing the complementing gene L4-100K

For stable and random transfection, the complementing plasmid pBSK-CMV- TPLIn-100K and a selection marker encoding the puromycin resistance gene were linearized. Therefore, 30 g of pBSK-CMV-TPLIn-100K was restriction digested using Sma\, a double cutter resulting in fragments of 3821 bp and 2869 bp, to remove backbone sequences.

HeLa-t cells (passage 6) were seeded 24 h prior transfection on 6 cm dishes at a density of 1 E6 cells/dish. In total 6 g linearized DNA in a molar ratio of 15:1 target vector to selection marker was transfected using calcium phosphate transfection method as followed: DNA was mixed with 150 μΙ 270 mM CaCI ₂ ,150 μΙ 2x HEBS (50mM Hepes, 280 mM NaCI, 1 .5 mM Na ₂ HPO , pH 7.1 ) were added, reaction mix was incubated for 20 min at room temperature and then added slowly onto the cells. Cells were incubated for 20 h at 35°C, 3% CO ₂ and then shifted to 37°C, 5% CO ₂ . 24 - 30 h post transfection cells from one 6 cm dish were expanded to two 15cm-dishes. Selection pressure using complemented culture media containing 0.25 g puromycin was started 24 h post expansion. Medium change was performed once in every two days. 10 days after selection start, 36 cell clones were picked and transferred to 24-Well plates, cultivated in 0.5 ml/well selection medium. Clones were kept under selection pressure and expanded sequentially over 6-Welll plates to 6 cm dishes, once they reached 80% confluency on the plates.

III.2 Expression analysis of integrated 100K

Gene expression of stably integrated 100K by positive transfectants was analyzed via Western blot. Therefore, cells were seeded in 6-Well plates and harvested at confluency of about 80% using TrypLE and prepared as protein samples. 50 g protein were loaded on 10% BIS-Tris gels for PAGE in MOPS buffer additionally containing 0.98 % sodium-bi-sulfite. Proteins were transferred on PVDF membrane 0.45 μιτι via tank blotting using Towbin buffer comprising 20 % methanol. Membranes were blocked in 5 % milk powder dissolved in 0,1 % Tween-TBS, over night at 4°C. Subsequently, membranes were incubated with 1 ^st antibody diluted 1 :100 in said blocking buffer at 4°C over night. After three rounds of washing, membranes were treated with 2 ^nd antibody Anti-Rabbit IgG peroxidase HRP produced in goat (Sigma) diluted 1 :10000 in 5% milk powder in 0,1 % Tween-TBS. Detection was done at AGFA CP 1000 via Pierce West Pico Chemoluminescence Substrate using GE Healthcare Amersham Hyperfilms. One clone, designated HeLa-t 6.1 1 , showed definite 100K expression and would be used for complementation of the adenovirus mutant deleted in L4-100K.

Furthermore, this cell clone was tested for stability by long-term experiments using concentrations of the selection agent puromycin 0.0 pg/ml, 0.25 pg/ml, 0.5 g/ml and I pg/ml, to which cells were exposed over 35 passages and afterwards would be tested for 100K expression.

IV. Adenovirus deletion mutant Δ100Κ Virus Production

IV.1 Virus rescue/production after bacmid transfection

HeLa-t 6.1 1 cells were seeded on 6cm dishes at a density of 1 E6 cells/dish in selection medium. Bacmid DNA encoding the adenovirus deletion mutant Δ100Κ was linearized via Swa\ restriction digestion, removing the vector backbone from the DNA fragment containing the mutant virus DNA with free adenoviral terminal repeats. After restriction digestion, 60 g of DNA were purified via phenol/chlorophorm extraction with subsequent ethanol/sodium acetate precipitation. Cells were transfected 24 h post seeding using laboratory's PEI in a ratio of 60 μΙ 7.5 mM PEI per 5 g DNA. Transfection mixes were prepared in 150mM NaCI as total volumes of 250 μΙ per DNA-reaction mix and PEI-reaction mix, each. 24 h post transfection medium change was performed. Cells were cultivated in medium without selection pressure during virus amplification and expanded into larger culture formats to avoid overgrowing. At day 7 post transfection, cells did not show cytopathic effect (CPE) but severe viability loss was observed. Therefore, cells were harvested completely (medium + cells) by scraping and lysed by three freeze and thaw cycles to re-infect HeLa-t 6.1 1 cells seeded in a 6cm dish (= 1 ^st amplification step). 72 h post re-infection, those cells showed CPE and were harvested for the 2 ^nd amplification step in the same manner as previously, but only half of the lysate was used to re-infect two 15cm dishes of HeLa-t 6.1 1 cells. For the 3 ^rd amplification step 2 x 15 cm dishes a 3E6 cells/dish were infected with 250 μΙ lysate obtained from the 2 ^nd amplification step.

Furthermore, virus mutant analysis was performed during amplification using Adeno-X™ Rapid Titer Kit (Clontech), Dot blot analysis and multiple re-infections of non-complementing cells, to characterize produced virus and possible revertants.

IV.2 Adenovirus deletion mutant A100K preparation/purification

For final preparation, the virus lysates from the second and third amplification step were pooled and used to re-infect 1 1 x 15cm dishes of HeLa-t 6.1 1 , seeded at a density of 5E6 cells/dish. Previously, on 24-Well plate format, the optimal amount of virus lysate had been titrated to obtain optimal CPE 48 h post infection. According to that titration experiment, 150 μΙ virus lysate per 15 cm dish were sufficient to obtain CPE 48 h post infection. Cells were cultivated in medium without selection pressure and incubated at 37°C, 5% CO2 _, for 48 h. After that time, cells showed complete CPE and were harvested completely together with the supernatant and centrifuged at 400 xg, 4°C for 10 min. Pellet was resolved in 3 ml HEPES pH 8 (50 mM Hepes, 150mM NaCI). Virus was released via three freeze and thaw cycles (liquid nitrogen, water bath 37°C) and cell debris removed by subsequent centrifugation at 4400 rpm for 10 min.

CsCI step gradient ultracentrifugation purification was performed to obtain purified virus stocks. For the first discontinous CsCI-gradient, virus lysate solution was layered on two CsCI-buffers comprising the densities 1 .41 g/ml and 1 .27 g/ml, and centrifuged for 2 h at 32 000 rpm at 4°C, using a Sorvall Discovery 90SE Hitachi Ultracentrifuge.

Subsequently, concentrated virus was extracted from the gradient and applied for the second continuous CsCI gradient ultracentrifugation for further purification. Therefore, extracted virus was mixed with CsCI-buffer pH 7.5 comprising a density of 1 .34 g/ml and centrifuged for 20 h at 32 000 rpm at 4°C. After centrifugation, virus was extracted and added to HEPES pH 8.0. Virus was desalted via size exclusion chromatography using PD-10 columns (GE Healthcare). Purified vector particles were supplemented with 10% glycerol and stored in aliquots at -80°C.

IV.3 Adenovirus deletion mutant A100K characterization

Produced adenovirus deletion mutant Δ100Κ was verified by several analyses during amplification steps and subsequent to virus purification.

Viral DNA was isolated from virus lysates from re-infected cells during the amplification steps and from purified virus using Qiagen QIAmp DNA Mini Kit. Isolated DNA was controlled via restriction digestion with subsequent agarose gel electrophoresis.

Since virus progeny of the mutant should only be possible on cells complementing the deletion defect, no virus amplification and thus no cytopathic effect (CPE) should occur in cells not carrying the complementing gene. Therefore, three rounds of re-infections on non-complementing HeLa and A549 cells using different amounts of non-purified virus lysates and different MOIs of virus stock were done to exclude possible reversion of deletion and to confirm replication-deficiency. All validation steps showed no CPE.

Photometric analysis was performed to determine physical titer, purity and to some extend integrity. Additionally, to evaluate potency and quality of produced virus, complementing cells were analyzed via Slot Blot to determine the infectious titer.

V. Adenovirus deletion mutant Δ100Κ as helper virus for rAAV production

V.1 Transient rAAV production cells using Adenovirus deletion mutant A100K as helper virus

A549 cells were seeded in 6cm-dishes at a density of 4E4 cells/cm ² and transfected 24 h post seeding via single-plasmid transfection with one plasmid, designated "All-in-One", encoding for rAAV vector + rep + cap. Directly after transfection, cells were infected with helper virus Ad5A100K pMOl 500 and as a reference with Adenovirus type 5 wildtype pMOl 500. Cells were incubated at 37°C, 5% CO ₂ for 48 h. Microscopy of cells revealed CPE (=cytopathic effect) on cells infected with Adwt. As expected, little CPE was observed on cells infected with Ad5A100K, too. Since L4-100K is a very late protein, the naturally occurring life cycle of adenovirus was not interrupted until maturation and virus assembly, thus most viral proteins were already expressed leading to the cytopathic effect in cells.

Cells were harvested via scraping and lysed by three freeze and thaw cycles (liquid nitrogen, water bath 37°C) with subsequent centrifugation at 3700 xg for 10 min to remove cell debris. In case of Adwt infection, helper virus was inactivated by incubation at 56°C for 30 min. Non-purified rAAV lysates were analyzed via qPCR to evaluate the genomic titer.

For qPCR 30 μΙ diluted 10 ^"2 rAAV lysate was treated with 10 U recombinant DNase I (Roche) for 3 hours at 37°C water bath to remove genomic and non-packaged vector DNA. Afterwards, 30 μΙ 400mM NaOH was added for 45 min at 65°C to inactivate DNase and denature vector particles. For efficient PCR, sample pH was neutralized by adding 30μΙ 400 mM HCI and were finally diluted 12.5 ^"1 in nuclease- free water.

Amplification was performed in a total volume of 25 μΙ using 2 X QuantiFast™ SYBR ^® Green PCR Mix,

100 nM forward primer 5'-GGAACCCCTAGTGATGGAGTT-3' (SEQ ID NO: 14), 300 nM reverse primer 5'-CGGCCTCAGTGAGCGA-3' (SEQ ID NO: 15)

and 5 μΙ template. PCR conditions were as followed: initial heat activation of polymerase at 95 °C for 5 min; 39 cycles of denaturation at 95 °C for 10 s and annealing/extension at 60 °C for 30 s; followed by a temperature gradient of 1 °C s ^"1 from 65 to 95 °C.

Results showed that Ad5A100K deletion mutant efficiently provided helper functions for rAAV production. Transiently produced rAAV in A549 led to titers around 5x10 ⁰⁹ vector genomes per ml (vg/ml), indicating a helper efficiency comparable to Adenovirus wildtype (Figure 4). Calculations revealed yields of about 1 .7x10 ⁴ rAAV vectors per cell.

V.2 rAAV production on stable producer cell using Adenovirus deletion mutant A100K as helper virus

In contrast to transient rAAV production where the components for rAAV packaging are introduced to the cell via co-transfection of three or two plasmids encoding the required elements for replicase (rep genes) and structure proteins (cap genes) and the vector transgene cassette itself with subsequent delivery of helper functions via infection, a stable producer cell line harbors the entire set of components, stably integrated into its genome. Therefore, rAAV production is initiated after super-infection of this cell by a helper virus.

For rAAV production stable producer cells were seeded in 6cm-dishes at a density of 4E4 cells/cm ² and 24 h post seeding, cells were infected with helper virus Ad5A100K pMOI 500 and as a reference with Adenovirus type 5 wildtype pMOI 500. Cells were incubated at 37°C, 5% CO ₂ for 48 h. Microscopy of cells revealed CPE on cells infected with Adwt but no cytopathic effect was observed on cells infected with Ad5A100K.

Cells were harvested via scraping and lysed by three freeze and thaw cycles (liquid nitrogen, water bath 37°C) with subsequent centrifugation at 3700 xg for 10 min to remove cell debris. In case of Adwt infection, helper virus was inactivated by incubation at 56°C for 30 min. Non-purified rAAV lysates were analyzed via qPCR to evaluate the genomic titer.

For qPCR 30 μΙ diluted 10 ^"2 rAAV lysate was treated with 10 U recombinant DNase I (Roche) for 3 hours at 37°C water bath to remove genomic and non-packaged vector DNA. Afterwards, 30 μΙ 400mM NaOH was added for 45 min at 65°C to inactivate DNase and denature vector particles. For efficient PCR, sample pH was neutralized by adding 30μΙ 400 mM HCI and were finally diluted 12.5 ^"1 in nuclease- free water. Amplification was performed in a total volume of 25 μΙ using 2 X QuantiFast SYBR ^® Green PCR Mix,

100 nM forward primer 5'-GGAACCCCTAGTGATGGAGTT-3'(SEQ ID NO: 16), 300 nM reverse primer 5'-CGGCCTCAGTGAGCGA-3' (SEQ ID NO: 17)

and 5 μΙ template. PCR conditions were as followed: initial heat activation of polymerase at 95 °C for 5 min; 39 cycles of denaturation at 95 °C for 10 s and annealing/extension at 60 °C for 30 s; followed by a temperature gradient of 1 °C s ^"1 from 65 to 95 °C.

Results showed that Ad5A100K deletion mutant provided helper functions for rAAV production. rAAV produced in stable A549 producer cells after superinfection with helper virus led to titers of about 5x10 ⁰⁸ vector genomes per ml (vg/ml), around 1 log lower compared to yields obtained with Adenovirus wildtype. Calculations revealed yields of about 2x10 ³ rAAV vectors per cell.

B. Life-cycle-defective Ad5 mutant deleted in the 52/55K protein

I. Generation of Adenovirus 5 Deletion Mutant Δ52/55Κ on DNA Level

/.1 Rationale for the Ad5 A52/55K deletion mutant

The L1 -52/55-kDa proteins are known to be essential for the encapsidation of viral DNA into pre-formed virions.

Therefore, one objective of the present invention is to delete nearly the entire sequence encoding for the L1 -52/55kDa-protein to use it as helper virus for rAAV production (Figure 6).

The N-terminal 1 134 bp within the 52/55kDa encoding sequence of 1248 bp length were deleted from position 1 1050 nt to 12184 nt according to the NCBI database reference AC_000008.1 Human Adenovirus 5 complete genome (coding sequence 52/55K: nt 1 1050 - nt 12297; SEQ ID NO: 46).

Table 4

deletion according to Human Adenovirus 5 NCBI AC_000008.1 complete genome

...TTGCAAATTCCTCCGGAAACAGGGACGAGCCCCTTTTTTGCTTTTCCCAG_[Ant11 050-

-12184] _CAGCTGGGGCCGGACCTGGGCTGGCGGTGGCACCCGCGCGCGCTGGCAAC... (SEQ ID NO: 18)

According to this deletion region, overlapping homologous sequences with the gene encoding the 52/55kDa within the complementing cell line, for virus production, were avoided, thus reducing the risk of homologous recombination between cell and virus, which could lead to revertants.

1.2 Cloning ofAd5 A52/55kDa The adenovirus deletion mutant A52/55kDa was generated using Homologous Recombination Gene Bridges Counter Selection Bac Modification Kit by RED ^® /ET ^® Recombination according to manufacturer's instructions.

The template DNA for insertion of the deletion defect was an adenovirus wildtype encoding bacmid pBELO66. Bacteria used for bacmid modifications were E.coli DHI OBeta. Deletion region within the bacmid was located from nt 10610 to nt 1 1744.

For the first and second RED®/ET® recombination step following primers were designed:

Table 5

Ad5 mutant 52/55K (intermediate): 50 bp (1 1000 -1 1049) 52/55K left to deletion + 24 bp rpSLneo for integration into rpSLneo cassette (italics)

TTGCAAATTCCTCCGGAAACAGGGACGAGCCCCTTTTTTGCTTTTCCCAGGGCCrGGrGA rGArGGCGGGArCG

(SEQ ID NO: 19)

Ad5 mutant 52/55K (intermediate): 50 bp (12185 -12234) 52/55K right to deletion + 24 bp rpSLneo for integration into rpSLneo cassette (italics)

GTTGCCAGCGCGCGCGGGTGCCACCGCCAGCCCAGGTCCGGCCCCAGCTGrCAGA¾GA� �CrCGrCA¾GA¾GGCG

(SEQ ID NO: 20)

M2: Ad5 mutant 52/55K, deletion No. 1 1050-12184

TTGCAAATTCCTCCGGAAACAGGGACGAGCCCCTTTTTTGCTTTTCCCAGCAGCTGGGGC CGGACCTGGGCTG GCGGTGGCACCCGCGCGCGCTGGCAAC

(SEQ ID NO: 21)

Bacterial amplification of accomplished bacmid was done in E.coli DHI OBeta and purified via Qiagen Large Construct Bacmid Preparation Kit according to manufacturer's protocol including the deviation that no exonuclease digestion was performed. II. Cloning of plasmid DNA encoding Ad5 "L1 -52/55K" for the complementing cell line

To produce life-cycle-defective Adenovirus mutants that carry a deletion in a crucial gene during life-cycle as virus particles, a complementing cell line expressing that deleted gene is necessary to get virus amplification and progeny. These produced virus particles are then life-cycle-defective on non-complementing cell lines. 11.1 Amplification of the target gene "L1-52/55K" as insert for the complementing plasmid

The complementing gene for the Adenovirus deletion mutant Δ52/55Κ was extracted from the bacmid pGS66 encoding the Ad5 genome sequence w/o E1 via Polymerase-Chain-Reaction (PCR) using primers additionally encoding endonuclease-restriction sites Nhe\ and EcoRV for further cloning steps (underlined).

Table 6

Ad5 52K Nhe\ Kozak forward

ataGCTAGCgaccATGCATCCGGTGCTGCGGCAGAT (SEQ ID NO: 22)

Ad5 52K EcoRV reverse

agtctGATATCTTAGTACTCGCCGTCCTCTGGCTCGTAC (SEQ ID NO: 23)

The amplified fragment was restriction-digested using Nhe\ and EcoRV. is transiently transfected with or has stably integrated a nucleic acid comprising the sequence of SEQ ID NO: 3, optionally under the control of an inducible promoter, such as a tetracycline-inducible promoter, or a promotor which drives less strong expression relative to the cytomegalovirus (CMV) promoter, preferably the human phosphoglycerate kinase (hPGK) promoter. This fragment represented the insert encoding 52/55kDa (Figure 7; SEQ ID NO: 2) to be introduced into a plasmid vector for subsequent bacterial amplification and introduction of the complementing gene into cells.

11.2 Preparation of complementing plasmid "pTRE-Tight-BI-AcGFP1-52/55K"

The generated fragment encoding 52/55K obtained from pGS66 via PCR amplification was used in several approaches to create a complementing cell line. Therefore, the fragment was first cloned in intermediate plasmids either carrying a strong cytomegalovirus derived promoter (CMV) or a weaker human phosphoglycerate kinase promotor (hPGK) for constitutive gene expression with subsequent introduction into A549 cells either via two-plasmid co-transfection of selection marker and expressing vector or via single-plasnnid transfection after additional cloning procedures to obtain plasmids encoding both selection marker and target gene. However, these approaches did not result in cell clones expressing the 52/55K gene due to presumed epigenetic silencing. The inability to create cells constitutively expressing the 52/55K gene indicated some cytotoxicity of that protein and therefore possibly causing a negative selection pressure on positively expressing cells. The next approach focused on an inducible 52/55K gene expression in stable cell clones. An inducible expression system would lead to the possibility to solely express the gene of interest for the time of mutant production hopefully reducing the risk of silencing and increasing cell viability, cell line stability and steady expression levels after induction. The generation of the double-stable cell line was based on Hek293TetON (Clontech). The target gene 52/55K was integrated into the MCS of the second generation vector pTRE-Tight- BI-AcGFP1 (#631066). According to Clontech Vector Information, PR083616; published August 20, 2010: "pTRE-Tight-BI-AcGFP1 is a bidirectional TRE-Tight plasmid that can be used to inducibly express a reporter green fluorescent protein (AcGFPI ) along with a gene of interest with our Tet-On and Tet-Off Gene Expression Systems and Cell Lines. pTRE-Tight-BI-AcGFP1 contains a modified Tet response element, which consists of seven direct repeats of a 36 bp sequence that contains the 19 bp tet operator sequence (tetO). The two mini CMV promoters, which lack the enhancer that is part of the complete CMV promoter, flank the TREmod. pTRE-Tight-BI-AcGFP1 encodes a variant of wild-type Aqueorea coerulescens green fluorescent protein (AcGFPI ). pTRE-Tight-BI- AcGFPI contains a multiple cloning site (MCS) downstream of the Bl-Tet- responsive Ptight promoters".

The Hek293TetON cell line was cultured in MEMa complemented with 10% FCS (heat-inactivated, Hyclone), 1 x GlutaMax (gibco) and 100pg/nnl geneticin.

The 52/55kDa-encoding fragment was introduced into the MCS of the tetracycline- inducible TetON vector pTRE-Tight-BI-AcGFP1 via Nhe\ and EcoRV.

11.3 Analysis and characterization of cloned "pTRE-Tight-BI-AcGFP1-52/55K"

Prior to stable transfection into Hek293TetON cells to generate a double-stable TetON inducible cell line expression 52/55K, the cloned plasmid was transiently analyzed for gene expression. Therefore, Hek293TetON were seeded on 6-Well plates in a density of 1 E5 cells/cm ² and transfected 24 h post seeding using Polyplus PEIPro I mg/ml in a ratio of 2:1 to DNA. For transfection in 6-Well plate format, 3 g total DNA were transfected, preparing transfection reaction mixes in non-complemented MEMa (gibco) in a total volume of 200 μΙ (100 μΙ DNA-mix, 100 μΙ PEI-mix). About 4 - 6 h after transfection, medium was exchanged to induction-medium consisting of previously described culture medium, additionally containing 1 g/ml doxycycline. Cells were harvested 24h and 48h after induction using TrypLE and centrifuged at 200 xg for 5 - 10 min. Pellets were used for cDNA analysis and Western blotting. For cDNA analysis total RNA was isolated via Qiagen RNeasy Plus Mini Kit according to manufacturer's protocol, using Qiagen QIA shredder to homogenize cells, and eluted in 50μΙ nuclease-free water. cDNA was synthesized from 1 μΙ of isolated RNA using Qiagen Omniscript Reverse Transcriptase Kit according to manufacturer's instructions. PCR priming 52/55K gene was performed in a total volume of 50 μΙ using Qiagen HotStar Taq Polymerase Kit as followed: 1x PCR buffer, 1 x Q-solution, 200 μΜ dNTPs (each),

200 nM forward primer 5'-ATGCATCCGGTGCTGCGGC-3' (SEQ ID NO: 24), 200 nM reverse primer 5'-TTAGTACTCGCCGTCCTCTGG-3' (SEQ ID NO: 25) and 5 μΙ of cDNA sample. Amplification was performed under following conditions: initial heat activation at 95°C for 15 min, 35 cycles of denaturation at 94°C for 30 sec, annealing at 58°C for 30 sec, elongation at 72°C for 3 min, followed by a final extension step at 72°C for 5 min. Products were visualized via 1 % agarose gel electrophoresis, showing positive signals at 1 .25 kb (Figure 8 A).

For Western blotting, pelleted samples were lyzed in 50 μΙ lysis buffer (50 mM Tris pH 7,5; 250 mM sucrose; 1 mM EDTA; 1 mM EGTA; 1 % Triton-X, 1 protease- inhibitor cocktail tablet (Roche)) for 1 - 3 h on ice, vortexing once in a while, and then centrifuged at 14 000 rpm, 4°C for 30 min to remove cell debris. Supernatant was complemented with SDS loading buffer containing β-mercaptoethanol. Determination of protein concentration and normalization was not performed due to focusing solely on a qualitative answer towards the question of gene expression. For western blot analysis, 25 μΙ sample were loaded on BioRad Mini- Protean ^® Gels TGX for gel electrophoresis at 120 V for 1 -3 h using Tris-Glycin buffer. Proteins were transferred on PVDF 0.2 μιτι membrane via tank blotting at 100 V for 1 h using Towbin buffer containing 20 % methanol. Positive transfer was confirmed via Ponceau-S staining. Membranes were blocked for 1 h at RT using Roth Roti ^® Block. After blocking, membranes were incubated over night at 4°C, 50 rpm, with 1 ^st antibody crt_1 15K 52/55K Rabbit 414 diluted 1 :1000 in 5% milk powder dissolved in 0.1 % PBS-Tween. Next day, subsequent to three rounds of washing using 0.1 % PBS-Tween, membranes were treated with 2 ^nd Anti-Rabbit IgG-peroxidase HRP-labelled antibody (Sigma) diluted 1 :5000 in 5% milk powder dissolved in 0.1 % PBS-Tween, for 3 h at RT. Detection was performed via AGFA CP 1000 using Pierce West Pico ECL Chemoluminescence Substrate Kit and GE Healthcare Amersham Hyperfilms.

Both assays revealed strong gene expression of 52/55K after induction, however additionally showed some leakiness of the pTRE-Tight promoter due to detectable signals in non-induced cells (Figure 8 B). This leakiness should be reduced in stably transfected cells, since the amount of DNA is much higher when transiently introduced than genomically integrated.

III. Generation of Inducible complementing cell line for AL1 -52/55k Mutant Virus production

111.1 Generation and selection of stable cell clones expressing L1-52/55K subsequent to induction

For stable and random transfection, the complementing plasmid pTRE-Tight-BI- AcGFP1 -52/55K and a selection marker encoding the puromycin resistance gene were linearized. Therefore, pTRE-Tight-BI-AcGFP1 -52/55K was restriction digested using Pvu\, a single cutter linearizing the plasmid within the ampicillin resistance gene cassette and for that reason leaving extended overhanging sequences on both ends to reduce loss of information due to DNA breaks during transfection and genomic integration.

Hek293TetON cells (passage 1 1 ) were seeded 24 h prior transfection on 6 cm dishes in a density of 1 E5 cells/cm ² and cultivated in MEMa + 10% FCS + 1 X GlutaMax + 100 g/ml geneticin. In total 6 g linearized DNA in a molar ratio of 20:1 target vector to selection marker were transfected using PEIPro Polyplus in a concentration of 2 g PEI per 1 g DNA. 24 - 48 h post transfection cells from one 6 cm dish were expanded to two 15cm-dishes. Selection pressure using complemented culture media containing 1 g puromycin was started 96 h post expansion, when cells grew adherently again and showed viable morphology. Medium change was performed once in every two days. 19 days after selection start, 5 cell clones were picked and transferred to 24-Well plates, cultivated in 1 ml/well selection medium. Clones were kept under selection pressure and cultivated up to 6 cm dishes.

111.2 Expression analysis of integrated TetON 52/55K

Gene expression of stably integrated inducible TetON 52/55K vector (= pTRE- Tight-BI-AcGFP1 -52/55K) was analyzed via Western blotting. Therefore, cell clones were seeded in duplicates in 6-Well plates in a density of 2E5 cells/cm ² . 24 h post seeding cell were induced using complemented MEMa medium without selection agent but containing 1 g/ml doxycycline for induction. Cells were analyzed via GFP- based fluorescence microscopy 48 h after induction and then harvested for Western blot analysis. Homogenous GFP-fluorescence was observed in induced cells and low to no GFP signal was observed in non-induced cells. Western blot was performed according to the transient expression analysis done previously on the cloned plasmid (see above). Here, strong 52/55K gene expression was detectable from induced cells (= +Dox), but leakiness of the promoter was not shown by non-induced cells (= -Dox). The selected five cell clones showed comparable potency in 52/55K expression to complement the deletion defect of the adenovirus mutant to rescue virus particle production (Figure 9).

C. Life-cycle-defective Ad 5 mutant deleted in the pre-terminal protein

I. Generation of Adenovirus 5 Deletion Mutant ApTP on DNA Level

1.1 Rationale Ad 5 ApTP deletion mutant

The terminal protein (TP) has its crucial role during initiation of adenoviral replication. As pre-terminal protein (pTP) it recognizes the terminus of the adenovirus DNA serving as a primer for DNA synthesis and forms a complex together with the adenoviral polymerase (AdPol) to enable replication of the viral genome. Deletion of essential gene sequences within the pTP should interrupt adenoviral life cycle at a very early phase - prior to genome replication. Almost the entire N-terminal coding sequence of 685bp was deleted up to the beginning of the tripartite leader sequence (TPL) located from nt 9904 to 10589 according to the reference in the database NCBI AC_000008.1 Ad5 complete genome (Figure 10). Table 7

pTP deletion in the human Adenovirus 5 NCBI AC_000008.1 complete genome:

...CCATGTCCTTGGGTCCGGCCTGCTGAATGCGCAGGGGGTCGGCCATGCCC_[An t9904-

-10589] _CTAGACCGTGCAAAAGGAGAGCGTGTAAGCGGGCACTCTTCCGTGGTCTG... SEQ ID NO: 26)

"The adenovirus tripartite leader is a 200-nucleotide-long 5' noncoding region which facilitates translation of viral mRNAs at late times after infection" (Dolph et al., 1990). According to this deletion region, overlapping homologous sequences with the gene encoding the pTP within the complementing cell line, for virus production, were avoided, thus reducing the risk of homologous recombination between cell and virus, which could lead to revertants.

Therefore, one object of the present invention is to prepare a ΔρΤΡ deletion mutation and to test its efficiency to support rAAV production. /.2 Cloning of Ad 5 Ap TP

The adenovirus deletion mutant ΔρΤΡ was generated using Homologous Recombination Gene Bridges Counter Selection Bac Modification Kit by RED ^® /ET ^® Recombination according to manufacturer's instructions.

The template DNA for insertion of the deletion defect was an adenovirus wildtype encoding bacmid pBELO66. Bacteria used for bacmid modifications were E.coli DHI OBeta. Deletion region within the bacmid was located from nt 9464 to nt 10149.

For the first and second RED ^® /ET ^® recombination step following primers were designed:

Table 8

Ad5 mutant pTP (intermediate): 50 bp (9853-9903) pTP left to deletion + 24 bp rpSLneo for integration into rpSLneo cassette (italics)

CCATGTCCTTGGGTCCGGCCTGCTGAATGCGCAGGCGGTCGGCCATGCCCGGCCrGGrGA rGArGGCGGGArCG

(SEQ ID NO: 27)

Ad5 mutant pTP (intermediat): 50 bp (10590-10640) pTP right to deletion + 24 bp rpSLneo for integration into rpSLneo cassette (italics)

CAGACCACGGAAGAGTGCCCGCTTACAGGCTCTCCTTTTGCACGGTCTAGrCAGA¾GA� �CrCGrCA¾GA¾GGCG

(SEQ ID NO: 28)

M1 : Ad5 mutant pTP, deletion No. 9904-10589

CCATGTCCTTGGGTCCGGCCTGCTGAATGCGCAGGCGGTCGGCCATGCCCCTAGACCGTG CAAAAGGAGAGCCTGTAAGCC GGCACTCTTCCGTGGTCTG (SEQ ID NO: 29)

Bacterial amplification of accomplished bacmid was done in DHI OBeta and purified via Qiagen Large Construct Bacmid Preparation Kit according to manufacturer's protocol including the deviation that no exonuclease digestion was performed.

II. Cloning of plasmid DNA encoding Ad5 terminal Protein (pTP) for the complementing cell line

To produce Adenovirus mutants that carry a deletion in a crucial gene during life- cycle as virus particles, a complementing cell line expressing that deleted gene is necessary to get virus amplification and progeny. These produced virus particles are then replication-deficient on non-complementing cell lines. 11.1 Amplification of the target gene terminal protein (pTP) as insert for the complementing plasmid

The complementing gene for the Adenovirus deletion mutant ΔρΤΡ was extracted from the bacmid pGS66 encoding the Ad5 genome sequence w/o E1 via Polymerase-Chain-Reaction (PCR) using primers additionally encoding endonuclease-restriction sites Nhe\ and Not\ for further cloning steps. The forward primer additionally encoded for a Kozak sequence which was planned to be inserted ahead of the pTP.

Table 9

Ad5 terminal protein Nhe\ Kozak + 3AS 5'pTP forward

attGCTAGCaccATGGCCTTGAGCGTCAACGATTGCGCG (SEQ ID NO: 30)

Ad5 terminal protein A/of I reverse

aGCGGCCGCCTAAAAGCGGTGACGCGGGC (SEQ ID NO: 31) The amplified fragment was digested using Nhe\ and A/oil. This fragment represented the insert encoding pTP to be introduced into a plasmid vector for subsequent bacterial amplification and introduction of the complementing gene into cells.

11.2 Preparation of final complementing plasmid "pBSK-hPGK-pTP" - cloning of target gene pTP into backbone vector pBSK-hPGK

The generated PCT fragment encoding the pTP (SEQ ID NO: 3) produced in 11.1 was introduced into backbone vector pBSK-hPGK, containing the hPGK promoter, which had been prepared previously. The hPGK promoter was chosen due to its 'weaker' activity relative to e.g. CMV promoter, on the basis that high expression levels of pTP were assumed to have a cytotoxic effect. Successfully cloned "pBSK-hPGK-pTP" was amplified in E. coli XL-2 Blue to obtain material sufficient both for characterization and stable transfection.

III. Generation of complementing cell Line for ATP Mutant Virus production

///.1 Generation and selection of stable cell clones expressing pTP

For stable and random transfection, the complementing plasmid pBSK-hPGK-pTP and a selection marker encoding the puromycin resistance gene were linearized. Therefore, pBSK-hPGK-pTP was restriction digested using Xmn\, a single cutter linearizing the plasmid within the ampicillin resistance gene cassette and for that reason leaving extended overhanging sequences on both ends to reduce loss of information due to DNA breaks during transfection and genomic integration. A549 cells (passage 94) were seeded 24 h prior transfection on 6 cm dishes in a density of 1 E6 cells/dish. In total 6 g linearized DNA in a molar ratio of 10:1 target vector to selection marker were transfected using PEIPro Polyplus in a concentration of 1 g PEI per 1 g DNA. 48 h post transfection cells from one 6 cm dish were expanded to two 15cm-dishes. Selection pressure using complemented culture media containing 0.5 g puromycin was started 24 post expansion. Medium change was performed once in every two days. 10 days after selection start, 30 cell clones were picked and transferred to 6-Well plates, cultivated in 3 ml/well selection medium. Clones were kept under selection pressure and cultivated up to 6 cm dishes.

///.2 Expression analysis of integrated p TP

Gene expression of stably integrated pTP by positive transfectants was analyzed via PCR. Therefore, 3E5 cells were harvested using Trypsin and pelleted for total gDNA isolation using Qiagen QIAmp DNA Mini Kit according to manufacturer's instructions (Appendix A: Protocol for cultured cells).

PCR reactions were performed in a total volume of 25 μΙ using 600 ng gDNA, primer concentrations of 200nM each, 600μΜ dNTP, 1 X Thermo Pol Buffer and 1 U Taq DNA polymerase. Following primers were used: 5'- TGTAGCCTTTGAGCGCGA-3' (forward) (SEQ ID NO: 32); 5'- ACCATGATTACGCCAAGCTC-3' (reverse) (SEQ ID NO: 33). Amplification was performed under following conditions: initial heat activation at 95°C for 2 min, 28 cycles of denaturation at 95°C for 30 sec, annealing at 49°C for 30 sec, elongation at 68°C for 1 :25 min, followed by a final extension step at 68°C for 5 min. Molecular mass was calculated to 6,60E-09 ng/fragment and amount of template applied corresponded to 6pg/genome. As a reference circular plasmid DNA of pBSK-hPGK-pTP was used as serial 10 ^"1 dilution in concentrations from 6E6 to 6E3. In case of correct amplification products, PCR fragments in size of 1 1 13 bp were available on agarose gel electrophoresis. According to the calculation of 6pg template DNA per genome, selected stable cell clones indicated all to express the complementing gene pTP, leading to the assumption of a homogenous cell population. Selected cell clone A549 42.9 was cryoconserved as MCB and WCB. Maintenance cell culture was further done without selection pressure.

IV. Adenovirus deletion mutant ΔΤΡ Virus Production

IV.1 Virus rescue/production after bacmid transfection

A549 42.9 cells were seeded on 6cm dishes at a density of 1 E6 cells/dish in selection medium. Bacmid DNA encoding the adenovirus deletion mutant ΔρΤΡ was linearized via Swa\ restriction digestion, extracting the vector backbone from the sequence encoding the mutant to release adenoviral terminal repeats. After restriction digestion, 5 g of DNA was purified via phenol/chlorophorm extraction with subsequent ethanol/sodium acetate precipitation. Cells were transfected 24 h post seeding using laboratory's PEI in a ratio of 60 μΙ PEI per 5 g DNA. Transfection mixes were prepared in 150mM NaCI as total volumes of 250 μΙ per DNA-reaction mix and PEI-reaction mix, each. 24 h post transfection medium change was performed. Cells were kept in selection medium during virus amplification and expanded into larger culture formats to avoid overgrowing. At day 7 post transfection, cells showed cytopathic effect (CPE), indicating virus mutant rescue and virus amplification. Therefore, cells were harvested completely (medium + cells) by scraping and lysed by three freeze and thaw cycles to reinfect A549 42.9 cells seeded in a 15cm dish (= 1 ^st amplification step). 48 h post re-infection, those cells showed CPE and were harvested for the 2 ^nd amplification step in the same manner as previously, but only half of the lysate was used to reinfect two 15cm dishes of A549 42.9 cells. In total three amplification steps were performed with 2x 15 cm dishes a 7E6 cells/dish to obtain enough adenovirus for virus preparation.

IV.2 Adenovirus deletion mutant ApTP preparation/purification

For final preparation, the virus lysates from the second and third amplification step were pooled and used to re-infect 12 x 15cm dishes of A549 42.9 cells. Previously, on 24-Well plate format, the optimal amount of virus lysate had been titrated to obtain optimal CPE 48 h post infection. According to that titration experiment, the entire virus lysate from the amplification steps had been sufficient for 12 dishes of cells seeded to 70 - 80% growth confluency. Cells were kept in selection medium containing 0.5 g/ml puromycin, and incubated at 37°C, 5% CO2 _, for 48 h. After that time, cells showed complete CPE and were harvested completely together with the supernatant and centrifuged at 400 xg, 4°C for 10 min. Pellet was resolved in 3 ml HEPES pH 7,5 (50 mM Hepes, 150mM NaCI) Control plate showed no CPE. Virus was released via three freeze and thaw cycles (liquid nitrogen, water bath 37°C) and cell debris removed by subsequent centrifugation at 3000 rpm for 10 min.

CsCI step gradient ultracentrifugation purification was performed to obtain purified virus stocks. For the first discontinous CsCI-gradient, virus lysate solution was layered on two CsCI-buffers comprising the densities 1 .41 g/ml and 1 .27 g/ml, and centrifuged for 2 h at 32 000 rpm at 4°C, using a Sorvall Discovery 90SE Hitachi Ultracentrifuge. Subsequently, concentrated virus was extracted from the gradient and applied for the second continuous CsCI gradient ultracentrifugation for further purification. Therefore, extracted virus was mixed with CsCI-buffer pH 7.5 comprising a density of 1 .34 g/ml and centrifuged for 24 h at 32 000 rpm at 4°C. After centrifugation, virus was extracted and desalted via size exclusion chromatography using PD-10 columns (GE Healthcare). Purified vector particles were supplemented with 10% glycerol and stored in aliquots at -80°C.

IV.3 Adenovirus Deletion Mutant ApTP Characterization

Produced adenovirus deletion mutant ΔρΤΡ was verified by several analyses during amplification steps and subsequent to virus purification.

Viral DNA was isolated from virus lysates from re-infected cells during the amplification steps and from purified virus using Qiagen QIAmp DNA Mini Kit. Isolated DNA was controlled via restriction digestion using Hindlll with subsequent agarose gel electrophoresis.

Since virus progeny of the mutant should only be possible on cells complementing the deletion defect, no virus amplification and thus no cytopathic effect (CPE) should occur in cells not carrying the complementing gene. Therefore, three rounds of re-infections on non-complementing A549 cells using different amounts of non-purified virus lysates and different MOIs of virus stock were done to exclude possible reversion of deletion and to confirm replication-deficiency. All validation steps showed no CPE.

Photometric analysis was performed to determine physical titer, purity and to some extend integrity. Additionally, to evaluate potency and quality of produced virus, complementing cells were titrated using different ratios of infectivity (MOI) and observed for optimal CPE 48 h p.i.

V. Adenovirus deletion mutant ATP as helper virus for rAAV Production

V.1 Transient rAAV production on A549 cells using Adenovirus deletion mutant ApTP as helper virus

A549 cells were seeded in 6cm-dishes at a density of 4E4 cells/cm ² and transfected 24 h post seeding via co-transfection of the three plasmids rAAV vector + rep + cap. Directly after transfection, cells were infected with helper virus Ad5ApTP pMOI 500 and as a reference with Adenovirus type 5 wildtype pMOI 500. Cells were incubated at 37°C, 5% CO ₂ for 48 h. Microscopy of cells revealed CPE on cells infected with Adwt but no cytopathic effect was observed on cells infected with Ad5ApTP. Cells were harvested via scraping and lysed by three freeze and thaw cycles (liquid nitrogen, water bath 37°C) with subsequent centrifugation at 3700 xg for 10 min to remove cell debris. In case of Adwt infection, helper virus was inactivated by incubation at 56°C for 30 min. Non-purified rAAV lysates were analyzed via qPCR to evaluate the genomic titer.

For qPCR 30 μΙ diluted 10 ^"2 rAAV lysate was treated with 10 U recombinant DNase I (Roche) for 3 hours at 37°C water bath to remove genomic and non-packaged vector DNA. Afterwards, 30 μΙ 400mM NaOH was added for 45 min at 65°C to inactivate DNase and denature vector particles. For efficient PCR, sample pH was neutralized by adding 30μΙ 400 mM HCI and were finally diluted 12.5 ^"1 in nuclease- free water.

Amplification was performed in a total volume of 25 μΙ using 2 X QuantiFast™ SYBR ^® Green PCR Mix, 100 nM forward primer 5'- GGAACCCCTAGTGATGGAGTT-3' (SEQ ID NO: 34), 300 nM reverse primer 5'- CGGCCTCAGTGAGCGA-3' (SEQ ID NO: 35) and 5 μΙ template. PCR conditions were as followed: initial heat activation of polymerase at 95 °C for 5 min; 39 cycles of denaturation at 95 °C for 10 s and annealing/extension at 60 °C for 30 s; followed by a temperature gradient of 1 °C s ^"1 from 65 to 95 °C.

Results showed that Ad5ApTP deletion mutant efficiently provided helper functions for rAAV production (Figure 12). Transiently produced rAAV in A549 via co- transfection and subsequent helper virus infection led to titers of about 10 ¹⁰ vector genomes per ml (vg/ml), indicating a helper efficiency comparable to Adenovirus wildtype. Calculations revealed yields of about 5x10 ⁴ rAAV vectors per cell.

V.2 rAAV production on stable producer cell using Adenovirus deletion mutant ApTP as helper virus

In contrast to transient rAAV production where the components for rAAV packaging are introduced to the cell via co-transfection of three or two plasmids encoding the required elements for replicase (rep genes) and structure proteins (cap genes) and the vector transgene cassette itself with subsequent delivery of helper functions via infection, a stable producer cell line harbors the entire set of components, stably integrated into its genome. Therefore, rAAV production is initiated after super-infection of this cell by a helper virus.

For rAAV production stable producer cells were seeded in 6cm-dishes at a density of 4E4 cells/cm ² and 24 h post seeding, cells were infected with helper virus Ad5ApTP pMOI 500 and as a reference with Adenovirus type 5 wildtype pMOI 500. Cells were incubated at 37°C, 5% CO ₂ for 48 h. Microscopy of cells revealed CPE on cells infected with Adwt but no cytopathic effect was observed on cells infected with Ad5ApTP.

Cells were harvested via scraping and lysed by three freeze and thaw cycles (liquid nitrogen, water bath 37°C) with subsequent centrifugation at 3700 xg for 10 min to remove cell debris. In case of Adwt infection, helper virus was inactivated by incubation at 56°C for 30 min. Non-purified rAAV lysates were analyzed via qPCR to evaluate the genomic titer.

For qPCR 30 μΙ diluted 10 ^"2 rAAV lysate was treated with 10 U recombinant DNase I (Roche) for 3 hours at 37°C water bath to remove genomic and non-packaged vector DNA. Afterwards, 30 μΙ 400mM NaOH was added for 45 min at 65°C to inactivate DNase and denature vector particles. For efficient PCR, sample pH was neutralized by adding 30μΙ 400 mM HCI and were finally diluted 12.5 ^"1 in nuclease- free water.

Amplification was performed in a total volume of 25 μΙ using 2 X QuantiFast™ SYBR®Green PCR Mix, 100 nM forward primer 5'- GGAACCCCTAGTGATGGAGTT-3' (SEQ ID NO: 36), 300 nM reverse primer 5'- CGGCCTCAGTGAGCGA-3' (SEQ ID NO: 37) and 5 μΙ template. PCR conditions were as followed: initial heat activation of polymerase at 95 °C for 5 min; 39 cycles of denaturation at 95 °C for 10 s and annealing/extension at 60 °C for 30 s; followed by a temperature gradient of 1 °C s ^"1 from 65 to 95 °C.

Results showed that Ad5ApTP deletion mutant efficiently provided helper functions for rAAV production (Figure 13). rAAV produced in stable A549 producer cells after super-infection with helper virus led to titers of about 10 ¹⁰ vector genomes per ml (vg/ml), indicating a helper efficiency comparable to Adenovirus wildtype. Calculations revealed yields of about 2x10 ⁴ rAAV vectors per cell.

D. Temperature-sensitive Ad 5 mutant point-mutated in the L4-100K and Hexon protein

I. Generation of Adenovirus 5 Temperature-Sensitive Double-Mutant with Mutations in 100K and hexon on DNA Level

/.1 Rationale Ad 5 temperature-sensitive mutant ts1 OOKtsHexon

A double-mutant carrying temperature-sensitive mutations in the L4-100k and hexon genes has not previously been generated. Since both genes do not function as adenoviral helper genes for a productive rAAV life-cycle, a virus having ts mutations in these genes would have the potency to be used as helper virus. In addition, the two ts mutations would essentially eliminate a reversion of the ts phenotype. Typical reversion frequencies of Adenovirus ts mutants are between 10 ^"6 to 10 ^"7 . Combining two ts mutants on one virus reduced the likelihood of reversion to 10 ^"12 to 10 ^"14 , which means to a completely non-ts phenotype. Adenovirus wild-type infection for rAAV production results in contaminated stocks of rAAV by adenovirus due to simultaneous adenovirus production. By rAAV production at non-permissive temperature, no adenovirus progeny should be formed, thus not contaminating the rAAV stocks produced.

Therefore, one object of the present invention is to prepare a double-mutant carrying both mutations and to test for its efficiency to support rAAV production. 1.2 Cloning of Ad 5 tslOOKtsHexon

The adenovirus temperature-sensitive mutant tsl OOKtsHexon was generated in two consecutive alteration steps using Homologous Recombination Gene Bridges Counter Selection Bac Modification by RED ^® /ET ^® Recombination according to manufacturer's instructions. First, an adenovirus mutant carrying the point- mutation for the ts100K was generated. Second, the temperature-sensitive point mutation for the hexon protein was additionally inserted into the mutant to obtain the temperature-sensitive double-mutant tsl OOKtsHexon, carrying the mutations TCC to CCC and GGC to GAT, located at positions nt 25456 - nt 25458 and nt 21 170 - nt 21 172 according to the reference NCBI AC_000008.1 Human Adenovirus type 5 complete genome.

1 .2.1 Generation of Intermediate Temperature-Sensitive Mutant ts100K

The template DNA for insertion of the ts100K defect was an adenovirus wildtype encoding bacmid pBELO66. Bacteria used for bacmid modifications were E.coli DHI OBeta. Region mutated on the bacmid comprised an exchange from TCC to CCC, representing the alteration from Serine (Ser466) to Proline (Pro466), and was located from nt 25016 to nt 25018.

For the first and second RED ^® /ET ^® recombination step to obtain the mutant carrying the temperature-sensitive mutation within the 100K, following primers were designed:

Table 10

Ad5 mutant H5ts1 B 100K (intermediate): 50 bp (25406-25455)

100K left from mutation + 24 bp rpSLneo for integration of rpSLneo cassette

(italics)

AACTGCTAAAGCAAAACTTGAAGGACCTATGGACGGCCTTCAACGAGCGCGGCCrGGrGA rGArGGCGGGArCG

(SEQ ID NO: 38) Ad5 mutant H5ts1 B 100K (intermediate): 50 bp (25459-25508)

100K right from mutation + 24 bp rpSLneo for integration of rpSLneo cassette

(italics)

GTTTTAAGCAGGCGTTCGGGGAAAATGATGTCCGCCAGGTGCGCGGCCACrCAGA¾GA� �CrCGrCA¾GA¾GGCG

(SEQ ID NO: 39)

M4: Ad5 H5ts1 B Mutant ts100K, mutation nt 25456 - nt 25458 (TCC (Ser466) to CCC (Pro466) mutated)

AACTGCTAAAGCAAAACTTGAAGGACCTATGGACGGCCTTCAACGAGCGCCCCGTGGCCG CGCACCTGGCGGACATCA TTTTCCCCGAACGCCTGCTTAAAA

(SEQ ID NO: 40)

Bacterial amplification of accomplished bacmid was done in E.coli DHI OBeta and purified via Qiagen Large Construct Bacmid Preparation Kit according to manufacturer's protocol including the deviation that no exonuclease digestion was performed.

1.2.2 Generation of Final Temperature-Sensitive Mutant ts100KtsHexon

The previously generated mutant Ad5ts100K represented the template DNA for the second round of bacmid modification using RED ^® /ET ^® recombination to additionally insert the tsHexon defect to obtain the temperature-sensitive double mutant Ad5ts100KtsHexon. Bacteria used for bacmid modifications were E.coli DHI OBeta. Region mutated on the bacmid comprised an exchange from GGC to GAT, representing the alteration from Glycin (Gly) to Aspartic acid (Asp), and was located from nt 20730 to nt 220732.

For the first and second RED ^® /ET ^® recombination step to obtain the double- mutant additionally carrying the temperature-sensitive mutation within Hexon, following primers were designed:

Table 1 1

Ad5ts147 Hexon ts intermediate: 50 bp left from nt 20730 (Hexon) + 24 bp rpSLneo for integration of rpSLneo cassette (italics)

acatgaccaaagactggttcctggtacaaatgctagctaactacaacattGGCCrGGrGA rGArGGCGGGArCG

(SEQ ID NO: 41)

Ad5ts147 Hexon ts intermediate: 50 bp right from nt 20732 (Hexon) + 24 bp rpSLneo for integration of rpSLneo cassette (italics)

aaggagtacatgcggtccttgtagctctctgggatatagaagccctggtarCAGA¾GA� �crCGrCA¾GA¾GGCG

(SEQ ID NO: 42)

Ad5ts147 Hexon ts: Hexon nt 2329 = AS 776: Gly (GGC) => Asp (GAT)

20730 - 20732 in pBEL066 = Mutation

Bacterial amplification of accomplished bacmid was done in E.coli DHI OBeta and purified via Qiagen Large Construct Bacmid Preparation Kit according to manufacturer's protocol including the deviation that no exonuclease digestion was performed. II. Adenovirus Temperature-Sensitive Mutant tsl OOKtsHexon Virus Production //.1 Virus rescue/amplification after bacmid transfection

The production of Adenovirus mutants carrying a temperature-sensitive point- mutation is not limited to a cell line complementing the defect, but to production at permissive temperatures. Therefore, A549 cells were seeded on 6cm dishes in a density of 5E5 cells/dish in a total volume of 5,5 ml DMEM medium (gibco #10938) complemented with 10% FCS and 1 X GlutaMax medium. Bacmid DNA encoding the adenovirus deletion mutant tsl OOKtsHexon was linearized via Swa\ restriction digestion at 25°C for 15 h, extracting the vector backbone of 6205 bp from the sequence encoding the mutant to release adenoviral terminal repeats. After restriction digestion, 60 g of DNA were purified via phenol/chlorophorm extraction with subsequent ethanol/sodium acetate precipitation, and 100 ng controlled via agarose gel electrophoresis. Cells were transfected 24 h post seeding using laboratory's PEI in a ratio of 62.5 μΙ 7,5 mM PEI per 5 g DNA. Transfection mixes were prepared in 150mM NaCI as total volumes of 250 μΙ per DNA-reaction mix and PEI-reaction mix, each, united and added to the cells after 10 min of incubation. In case of virus rescue, cells would show cytopathic effect several days after transfection, due to viral protein expression and amplification. 24 h post transfection medium change was performed. About 7 - 9 days after transfection, cells were harvested via TrypLE, and 1/3 was seeded on one 10 cm dish, whereas 2/3 were lyzed via three freeze and thaw cycles (liquid nitrogen, water bath 37°C) to re-infect A549 cells seeded on a 15 cm dish (= 1 ^st amplification). Cells were incubated at 32°C, 5% CO2. Three days later, cells showed CPE and were harvested for the 2 ^nd amplification step in the same manner as previously and the lysate for used to re-infect 4x 15cm dishes of A549 cells. During amplification steps, temperature-sensitivity was controlled additionally by using the lysate from amplification at 32°C to re-infect A549 cells seeded in 6cm dishes and cultivated at the non-permissive temperature of 39°C. Furthermore, possible revertants were analyzed by several amplification rounds, continuously performed at 39°C. In those controls, no virus should be observed. After three days of 2 amplification, cells were harvested completely, centrifuged at 300 x g for 5 min and the pellet dissolved in 4 ml PBS and lyzed via three freeze and thaw cycles with subsequent centrifugation at 4400 rpm for 10 min, to remove cell debris. The supernatant was the lysate for the infection of A549 cells for virus preparation.

11.2 Adenovirus ts mutant ts1 OOKtsHexon preparation/purification

For final preparation, the virus lysate from the second amplification step were used to re-infect 20 x 15cm dishes of A549 cells, seeded to a confluency of about 80%. Cells were incubated at 32°C, 5% CO ₂ , for 72 h. After that time, cells showed CPE and were harvested completely via scraping, together with the supernatant and centrifuged at 400 xg, 4°C for 10 min. Pellet was resolved in 6 ml PBS. Virus was released via three freeze and thaw cycles (liquid nitrogen, water bath 37°C) and cell debris removed by subsequent centrifugation at 4400 rpm for 10 min.

CsCI step gradient ultracentrifugation purification was performed to obtain purified virus stocks. For the first discontinuous CsCI-gradient, virus lysate solution was layered on two CsCI-buffers comprising the densities 1 .41 g/ml and 1 .27 g/ml, and centrifuged for 2 h at 32 000 rpm at 4°C, using a Sorvall Discovery 90SE Hitachi Ultracentrifuge.

Subsequently, concentrated virus was extracted from the gradient and applied for the second continuous CsCI gradient ultracentrifugation for further purification. Therefore, extracted virus was mixed with CsCI-buffer pH 7.5 comprising a density of 1 ,34 g/ml and centrifuged for 20 h at 32 000 rpm at 4°C. After centrifugation, virus was extracted and added to HEPES buffer pH 7.1 (150mM NaCI, 50mM HEPES). Virus was desalted via size exclusion chromatography using PD-10 columns (GE Healthcare), which previously were equilibrated five times with 5 ml HEPES buffer. Subsequently, previously extracted vector sample was loaded onto the columns and eluted with 5 ml HEPES buffer, collected in five fractions of 1 ml volume, wherein fraction two and three contained the vector. Purified vector particles were supplemented with 10% glycerol and stored in aliquots at -80°C. 11.3 Adenovirus Temperature-Sensitive Mutant ts1 OOKtsHexon Characterization

Produced adenovirus mutant ts1 OOKtsHexon was verified by several analyses subsequent to virus purification.

Viral DNA was isolated from purified virus using Qiagen QIAmp DNA Mini Kit and controlled via restriction digestion of 150 ng DNA with subsequent agarose gel electrophoresis. Photometric analysis was performed to determine physical titer, purity and to some extend integrity. Since virus progeny of the mutant should only be possible at permissive temperature, no virus amplification and thus no cytopathic effect (CPE) should occur in cells incubated at the non-permissive temperature of 39°C. Therefore, A549 cells were infected with purified virus using different ratios of infection and incubated at 37°C, 32°C and 39°C to analyze temperature-sensitivity of the virus mutant. As control, cells were infected with Ad5wt, respectively. Cytopathic effect occurred at all incubation temperatures, but was not observed in cells infected with mutant virus at temperatures of 37°C and 39°C, thus indicating, that the double-mutant carrying both ts100K and tsHexon mutations had a higher temperature-sensitivity than mutants carrying only one of both mutations which were known to be permissive at 37°C. Furthermore, stability was controlled by three rounds of re-infection at non-permissive temperature to analyze possible virus revertants during amplification.

Furthermore, quantitative analysis of temperature-sensitivity and determination of infectious particles were analyzed via Plaque Assay. Therefore, A549 cells were seeded in 6-Well plates in a density of 3,5x10 ⁵ cells/well and incubated at 32°C, 5%CO ₂ at 32°C. Cells were infected with Ad5ts100KtsHexon and Ad5wt as reference using infection rates of 1 E3, 1 E2 and 1 E1 particles/cell. Infected cells were incubated at 32°C for 4 hours, then an 0.75 % agarose gel overlay was prepared in culture medium and subsequently cells were further kept at 32°C or shifted to 37°C and 39°C, respectively. Next day a second overlay was performed onto the first agarose gel overlay to provide enough nutrition during the time of assay. Cells were incubated for 15 days and analyzed via microscopy once every two to three days. In cells infected with Ad5wt plaques emerged at day seven and showed complete CPE till day 9, independently to infection rate and incubation temperature. In cells infected with the double-mutant Ad5ts100KtsHexon plaques, thus CPE, was observed from day 7 till reaching complete CPE till day nine, at incubation temperature at 32°C and an infection rate of 1 E3 particles/cell . Infection rates of 1 E2 and 1 E1 reached complete CPE 13 days after infection. Cells incubated at 39°C did not develop plaques during all 15 days, confirming temperature-sensitivity. However, most striking was the observation that cells infected with Ad5ts100KtsHexon and incubated at temperatures of 37°C did not develop plaques at all, indicating that 37°C represents a non-permissive temperature for that double-mutant.

III. Transient rAAV Production on A549 cells using Ad5 tsl OOKtsHexon as helper virus A549 cells were seeded in 6cm-dishes at a density of 4E4 cells/cm2 and transfected 24 h post seeding either via single-plasmid transfection with one plasmid, designated "All-in-One", encoding for rAAV vector + rep + cap, or via co- transfection of three plasmids each encoding rAAV vector, rep, and cap in a molar ratio of 4:3:9. Directly after transfection, cells were infected with helper virus Ad5ts100KtsHexon pMOI 500 and as a reference with Adenovirus type 5 wildtype pMOI 500. rAAV production was performed at 37°C and 39°C, respectively, due to previous investigations indicating even 37°C to be non-permissive to the double- mutant. For rAAV production at 39°C, cells were incubated at 37°C, 5% CO ₂ for 1 h and then shifted to 39°C, 5%CO ₂ for 48 h. Microscopy of cells revealed CPE (=cytopathic effect) on cells infected with Adwt. As expected, little CPE was observed on cells infected with Ad5ts100KtsHexon, too. Since L4-100K is a very late protein playing a role in virion assembly and the hexon mutation results in a transport deficiency of hexon capsid proteins from cytoplasm to nucleus, the naturally occurring life cycle of adenovirus is not interrupted until maturation and virus assembly, thus most viral proteins are already expressed leading to the cytopathic effect in cells.

Cells were harvested via scraping and lysed by three freeze and thaw cycles (liquid nitrogen, water bath 37°C) with subsequent centrifugation at 3700 xg for 10 min to remove cell debris. In case of Adwt infection, helper virus was inactivated by incubation at 56°C for 30 min. Non-purified rAAV lysates were analyzed via qPCR to evaluate the genomic titer.

For qPCR 30 μΙ diluted 10-2 rAAV lysate was treated with 10 U recombinant DNase I (Roche) for 3 hours at 37°C water bath to remove genomic and non- packaged vector DNA. Afterwards, 30 μΙ 400mM NaOH was added for 45 min at 65°C to inactivate DNase and denature vector particles. For efficient PCR, sample pH was neutralized by adding 30μΙ 400 mM HCI and were finally diluted 12.5-1 in nuclease-free water.

Amplification was performed in a total volume of 25 μΙ using 2 X QuantiFastTM SYBR ^® Green PCR Mix, 100 nM forward primer 5'- GGAACCCCTAGTGATGGAGTT-3' (SEQ ID NO: 44), 300 nM reverse primer 5'- CGGCCTCAGTGAGCGA-3' (SEQ ID NO: 45) and 5 μΙ template. PCR conditions were as followed: initial heat activation of polymerase at 95 °C for 5 min; 39 cycles of denaturation at 95 °C for 10 s and annealing/extension at 60 °C for 30 s; followed by a temperature gradient of 1 °C s-1 from 65 to 95 °C.

Results showed that Ad5Ats100KtsHexon mutant efficiently provided helper functions for rAAV production. Transiently produced rAAV in A549 via co- transfection led to titers of about 5x10 vector genomes per ml (vg/ml) and of about 2x10 ⁰⁴ vectors per cell (vg/cell) (Figure 14). Production via single-plasmid transfection led to lower titers of about 2,5x10 ⁹ vg/ml and about 9,5x10 ⁰³ vg/cell (Figure 15). In comparison to Ad5wt both production methods showed about ½- fold lower yields using the Ad5ts100KtsHexon mutant.

LITERATURE

Dolph, P. J., J. T. Huang, und R. J. Schneider. .Translation by the Adenovirus Tripartite Leader: Elements Which Determine Independence from Cap-Binding Protein Complex". Journal of Virology 64, Nr. 6 (Juni 1990): 2669-77.

Gustin, K. E., und M. J. Imperiale. „Encapsidation of Viral DNA Requires the Adenovirus L1 52/55-Kilodalton Protein". Journal of Virology 72, Nr. 10 (Oktober 1998): 7860-70.

Hasson, T. B., P. D. Soloway, D. A. Ornelles, W. Doerfler, und T. Shenk. ..Adenovirus L1 52- and 55-Kilodalton Proteins Are Required for Assembly of Virions". Journal of Virology 63, Nr. 9 (September 1989): 3612-21 .

Hodges, B. L., H. K. Evans, R. S. Everett, E. Y. Ding, D. Serra, und A. Amalfitano. ..Adenovirus Vectors with the 100K Gene Deleted and Their Potential for Multiple Gene Therapy Applications". Journal of Virology 75, Nr. 13 (Juli 2001 ): 5913-20. doi:10.1 128/JVI.75.13.5913-5920.2001 .

Kauffman, R. S., und H. S. Ginsberg. ..Characterization of a Temperature- Sensitive, Hexon Transport Mutant of Type 5 Adenovirus". Journal of Virology 19, Nr. 2 (August 1976): 643-58.

Maxwell, I. H., F. Maxwell, und J. Schaack.„An Adenovirus Type 5 Mutant with the Preterminal Protein Gene Deleted Efficiently Provides Helper Functions for the Production of Recombinant Adeno-Associated Virus". Journal of Virology 72, Nr. 10 (Oktober 1998): 8371-73.

Oosterom-Dragon, E A, und H S Ginsberg. ..Characterization of two temperature- sensitive mutants of type 5 adenovirus with mutations in the 100,000-dalton protein gene." Journal of Virology 40, Nr. 2 (November 1981 ): 491-500.

Perez-Romero, Pilar, Kurt E. Gustin, und Michael J. Imperiale. ..Dependence of the Encapsidation Function of the Adenovirus L1 52/55-Kilodalton Protein on Its Ability to Bind the Packaging Sequence". Journal of Virology 80, Nr. 4 (Februar 2006): 1965-71 . doi:10.1 128/JVI.80.4.1965-1971 .2006. Schaack, J., X. Guo, und S. J. Langer. ..Characterization of a Replication- Incompetent Adenovirus Type 5 Mutant Deleted for the Preterminal Protein Gene". Proceedings of the National Academy of Sciences of the United States of America 93, Nr. 25 (10. Dezember 1996): 14686-91 .

Schaack, J., X. Guo, W. Y. Ho, M. Karlok, C. Chen, und D. Ornelles. ..Adenovirus Type 5 Precursor Terminal Protein-Expressing 293 and HeLa Cell Lines". Journal of Virology 69, Nr. 7 (Juli 1995): 4079-85.

Williams, J. F., Meera Gharpure, S. Ustacelebi, und Sylvia McDonald. ..Isolation of Temperature-sensitive Mutants of Adenovirus Type 5". Journal of General Virology 1 1 , Nr. 2 (1971 ): 95-101 . doi:10.1099/0022-1317-1 1 -2-95.

Wodrich, Harald, Tinglu Guan, Gino Cingolani, Dan Von Seggern, Glen Nemerow, und Larry Gerace.„Switch from Capsid Protein Import to Adenovirus Assembly by Cleavage of Nuclear Transport Signals". The EMBO Journal 22, Nr. 23 (1 . Dezember 2003): 6245-55. doi:10.1093/emboj/cdg614.

ADDITIONAL SEQUENCES

SEQ ID NO: 1 (L4-100K mutant)

ATGGAGTCAGTCGAGAAGAAGGACAGCCTAACCGCCCCCTCTGAGTTCGCCACCACCGCC TCCACCGATGCCGCCAACGC GCCTACCACCTTCCCCGTCGAGGCACCCCCGCTTGAGGAGGAGGAAGTGATTATCGAGCA GGACCCAGGTTTTGTAAGCG AAGACGACGAGGACCGCTCAGTACCAACAGAGGATAAAAAGCAAGACCAGGACAACGCAG AGGCAAACGAGGAACAAGTC GGGCGGGGGGACGAAAGGCATGGCGACTACCTAGATGTGGGAGACGACGTGCTGTTGAAG CATCTGCAGCGCCAGTGCGC CATTATCTGCGACGCGTTGCAAGAGCGCAGCGATGTGCCCCTCGCCATAGCGGATGTCAG CCTTGCCTACGAACGCCACC TATTCTCACCGCGCGTACCCCCCAAACGCCAAGAAAACGGCACATGCGAGCCCAACCCGC GCCTCAACTTCTACCCCGTA TTTGCCGTGCCAGAGGTGCTTGCCACCTATCACATCTTTTTCCAAAACTGCAAGATACCC CTATCCTGCCGTGCCAACCG CAGCCGAGCGGACAAGCAGCTGGCCTTGCGGCAGGGCGCTGTCATACCTGATATCGCCTC GCTCAACGAAGTGCCAAAAA TCTTTGAGGGTCTTGGACGCGACGAGAAGCGCGCGGCAAACGCTCTGCAACAGGAAAACA GCGAAAATGAAAGTCACTCT GGAGTGTTGGTGGAACTCGAGGGTGACAACGCGCGCCTAGCCGTACTAAAACGCAGCATC GAGGTCACCCACTTTGCCTA CCCGGCACTTAACCTACCCCCCAAGGTCTTGCCTACCACTCTGACATAATGGAAGACGTG AGCGGTGACGGTCTACTGGA GTGTCACTGTCGCTGCAACCTATGCACCCCGCACCGCTCCCTGGTTTGCAATTCGCAGCT GCTTAACGAAAGTCAAATTA TCGGTACCTTTGAGCTGCAGGGTCCCTCGCCTGACGAAAAGTCCGCGGCTCCGGGGTTGA AACTCACTCCGGGGCTGTGG ACGTCGGCTTACCTTCGCAAATTTGTACCTGAGGACTACCACGCCCACGAGATTAGGTTC TACGAAGACCAATCCCGCCC GCCAAATGCGGAGCTTACCGCCTGCGTCATTACCCAGGGCCACATTCTTGGCCAATTGCA AGCCATCAACAAAGCCCGCC AAGAGTTTCTGCTACGAAAGGGACGGGGGGTTTACTTGGACCCCCAGTCCGGCGAGGAGC TCAACCCAATCCCCCCGCCG CCGCAGCCCTATCAGCAGCAGCCGCGGGCCCTTGCTTCCCAGGATGGCACCCAAAAAGAA GCTGCAGCTGCCGCCGCCAC CCACGGACGAGGAGGAATACTGGGACAGTCAGGCAGAGGAGGTTTTGGACGAGGAGGAGG AGGACATGATGGAAGACTGG GAGAGCCTAGACGAGGAAGCTTCCGAGGTCGAAGAGGTGTCAGACGAAACACCGTCACCC TCGGTCGCATTCCCCTCGCC GGCGCCCCAGAAATCGGCAACCGGTTCCAGCATGGCTACAACCTCCGCTCCTCAGGCGCC GCCGGCACTGCCCGTTCGCC GACCCAACCGTAG

SEQ ID NO: 2 (L1 -52/55K mutant)

CAGCTGGGGCCGGACCTGGGCTGGCGGTGGCACCCGCGCGCGCTGGCAACGTCGGCGGCG TGGAGGAATATGACGAGGAC GATGAGTACGAGCCAGAGGACGGCGAGTACTAA

SEQ ID NO: 3 (pTP mutant)

CTAAAAGCGGTGACGCGGGCGAGCCCCCGGAGGTAGGGGGGGCTCCGGACCCGCCGGGAG AGGGGGCAGGGGC ACGTCGGCGCCGCGCGCGGGCAGGAGCTGGTGCTGCGCGCGTAGGTTGCTGGCGAACGCG ACGACGCGGCGGT TGATCTCCTGAATCTGGCGCCTCTGCGTGAAGACGACGGGCCCGGTGAGCTTGAGCCTGA AAGAGAGTTCGAC AGAATCAATTTCGGTGTCGTTGACGGCGGCCTGGCGCAAAATCTCCTGCACGTCTCCTGA GTTGTCTTGATAG GCGATCTCGGCCATGAACTGCTCGATCTCTTCCTCCTGGAGATCTCCGCGTCCGGCTCGC TCCACGGTGGCGG CGAGGTCGTTGGAAATGCGGGCCATGAGCTGCGAGAAGGCGTTGAGGCCTCCCTCGTTCC AGACGCGGCTGTA GACCACGCCCCCTTCGGCATCGCGGGCGCGCATGACCACCTGCGCGAGATTGAGCTCCAC GTGCCGGGCGAAG ACGGCGTAGTTTCGCAGGCGCTGAAAGAGGTAGTTGAGGGTGGTGGCGGTGTGTTCTGCC ACGAAGAAGTACA TAACCCAGCGTCGCAACGTGGATTCGTTGATATCCCCCAAGGCCTCAAGGCGCTCCATGG CCTCGTAGAAGTC CACGGCGAAGTTGAAAAACTGGGAGTTGCGCGCCGACACGGTTAACTCCTCCTCCAGAAG ACGGATGAGCTCG GCGACAGTGTCGCGCACCTCGCGCTCAAAGGCTACAGGGGCCTCTTCTTCTTCTTCAATC TCCTCTTCCATAA GGGCCTCCCCTTCTTCTTCTTCTGGCGGCGGTGGGGGAGGGGGGACACGGCGGCGACGAC GGCGCACCGGGAG GCGGTCGACAAAGCGCTCGATCATCTCCCCGCGGCGACGGCGCATGGTCTCGGTGACGGC GCGGCCGTTCTCG CGGGGGCGCAGTTGGAAGACGCCGCCCGTCATGTCCCGGTTATGGGTTGGCGGGGGGCTG CCATGCGGCAGGG ATACGGCGCTAACGATGCATCTCAACAATTGTTGTGTAGGTACTCCGCCGCCGAGGGACC TGAGCGAGTCCGC ATCGACCGGATCGGAAAACCTCTCGAGAAAGGCGTCTAACCAGTCACAGTCGCAAGGTAG GCTGAGCACCGTG GCGGGCGGCAGCGGGCGGCGGTCGGGGTTGTTTCTGGCGGAGGTGCTGCTGATGATGTAA TTAAAGTAGGCGG TCTTGAGACGGCGGATGGTCGACAGAAGCACCATGTCCTTGGGTCCGGCCTGCTGAATGC GCAGGCGGTCGGC CATGCCCCTAGACCGTGCAAAAGGAGAGCCTGTAAGCGGGCACTCTTCCGTGGTCTGGTG GATAAATTCGCAA GGGTATCATGGCGGACGACCGGGGTTCGAGCCCCGTATCCGGCCGTCCGCCGTGATCCAT GCGGTTACCGCCC GCGTGTCGAACCCAGGTGTGCGACGTCAGACAACGGGGGAGTGCTCCTTTTGGCTTCCTT CCAGGCGCGGCGG CTGCTGCGCTAGCTTTTTTGGCCACTGGCCGCGCGCAGCGTAAGCGGTTAGGCTGGAAAG CGAAAGCATTAAG TGGCTCGCTCCCTGTAGCCGGAGGGTTATTTTCCAAGGGTTGAGTCGCGGGACCCCCGGT TCGAGTCTCGGAC CGGCCGGACTGCGGCGAACGGGGGTTTGCCTCCCCGTCATGCAAGACCCCGCTTGCAAAT TCCTCCGGAAACA GGGACGAGCCCCTTTTTTGCTTTTCCCAGATGCATCCGGTGCTGCGGCAGATGCGCCCCC CTCCTCAGCAGCG GCAAGAGCAAGAGCAGCGGCAGACATGCAGGGCACCCTCCCCTCCTCCTACCGCGTCAGG AGGGGCGACATCC GCGGTTGACGCGGCAGCAGATGGTGATTACGAACCCCCGCGGCGCCGGGCCCGGCACTAC CTGGACTTGGAGG AGGGCGAGGGCCTGGCGCGGCTAGGAGCGCCCTCTCCTGAGCGGTACCCAAGGGTGCAGC TGAAGCGTGATAC GCGTGAGGCGTACGTGCCGCGGCAGAACCTGTTTCGCGACCGCGAGGGAGAGGAGCCCGA GGAGATGCGGGAT CGAAAGTTCCACGCAGGGCGCGAGCTGCGGCATGGCCTGAATCGCGAGCGGTTGCTGCGC GAGGAGGACTTTG AGCCCGACGCGCGAACCGGGATTAGTCCCCGTGGCGGCCGCCGACCTGGTAACCGCATAC GAGCAGACGGTGA ACCAGGAGATTAACTTTCAAGCGCGCGCACAAAAAGCTTTAACAACCACGTGCGTACGCT TGTGGCGCGCGAG GAGGTGGCTATAGGACTGATGCATCTGTGGGACTTTGTAAGCGCGCTGGAGCAAAACCCA AATAGCAAGCCGC TCATGGCGCAGCTGTTCCTTATAGTGCAGCACAGCAGGGACAACGAGGCATTCAGGGATG CGCTGCTAAACAT AGTAGAGCCCGAGGGCCGCTGGCTGCTCGATTTGATAAACATCCTGCAGAGCATAGTGGT GCAGGAGCGCAGC TTGAGCCTGGCTGACAAGGTGGCCGCCATCAACTATTCCATGCTTAGCCTGGGCAAGTTT TACGCCCGCAAGA TATACCATACCCCTTACGTTCCCATAGACAAGGAGGTAAAGATCGAGGGGTTCTACATGC GCATGGCGCTGAA GGTGCTTACCTTGAGCGACGACCTGGGCGTTTATCGCAACGAGCGCATCCACAAGGCCGT GAGCGTGAGCCGG CGGCGCGAGCTCAGCGACCGCGAGCTGATGCACAGCCTGCAAAGGGCCCTGGCTGGCACG GGCAGCGGCGATA GAGAGGCCGAGTCCTACTTTGACGCGGGCGCTGACCTGCGCTGGGCCCCAAGCCGACGCG CCCTGGAGGCAGC TGGGGCCGGACCTGGGCTGGCGGTGGCACCCGCGCGCGCTGGCAACGTCGGCGGCGTGGA GGAATATGACGAG GACGATGAGTACGAGCCAGAGGACGGCGAGTACTAAGCGGTGATGTTTCTGATCAGATGA TGCAAGACGCAAC GGACCCGGCGGTGCGGGCGGCGCTGCAGAGCCAGCCGTCCGGCCTTAACTCCACGGACGA CTGGCGCCAGGTC ATGGACCGCATCATGTCGCTGACTGCGCGCAATCCTGACGCGTTCCGGCAGCAGCCGCAG GCCAACCGGCTCT CCGCAATTCTGGAAGCGGTGGTCCCGGCGCGCGCAAACCCCACGCACGAGAAGGTGCTGG CGATCGTAAACGC GCTGGCCGAAAACAGGGCCATCCGGCCCGACGAGGCCGGCCTGGTCTACGACGCGCTGCT TCAGCGCGTGGCT CGTTACAACAGCGGCAACGTGCAGACCAACCTGGACCGGCTGGTGGGGGATGTGCGCGAG GCCGTGGCGCAGC GTGAGCGCGCGCAGCAGCAGGGCAACCTGGGCTCCATGGTTGCACTAAACGCCTTCCTGA GTACACAGCCCGC CAACGTGCCGCGGGGACAGGAGGACTACACCAACTTTGTGAGCGCACTGCGGCTAATGGT GACTGAGACACCG CAAAGTGAGGTGTACCAGTCTGGGCCAGACTATTTTTTCCAGACCAGTAGACAAGGCCTG CAGACCGTAAACC TGAGCCAGGCTTTCAAAAACTTGCAGGGGCTGTGGGGGGTGCGGGCTCCCACAGGCGACC GCGCGACCGTGTC TAGCTTGCTGACGCCCAACTCGCGCCTGTTGCTGCTGCTAATAGCGCCCTTCACGGACAG TGGCAGCGTGTCC CGGGACACATACCTAGGTCACTTGCTGACACTGTACCGCGAGGCCATAGGTCAGGCGCAT GTGGACGAGCATA CTTTCCAGGAGATTACAAGTGTCAGCCGCGCGCTGGGGCAGGAGGACACGGGCAGCCTGG AGGCAACCCTAAA CTACCTGCTGACCAACCGGCGGCAGAAGATCCCCTCGTTGCACAGTTTAAACAGCGAGGA GGAGCGCATTTTG CGCTACGTGCAGCAGAGCGTGAGCCTTAACCTGATGCGCGACGGGGTAACGCCCAGCGTG GCGCTGGACATGA CCGCGCGCAACATGGAACCGGGCATGTATGCCTCAAACCGGCCGTTTATCAACCGCCTAA TGGACTACTTGCA TCGCGCGGCCGCCGTGAACCCCGAGTATTTCACCAATGCCATCTTGAACCCGCACTGGCT ACCGCCCCCTGGT TTCTACACCGGGGGATTCGAGGTGCCCGAGGGTAACGATGGATTCCTCTGGGACGACATA GACGACAGCGTGT TTTCCCCGCAACCGCAGACCCTGCTAGAGTTGCAACAGCGCGAGCAGGCAGAGGCGGCGC TGCGAAAGGAAAG CTTCCGCAGGCCAAGCAGCTTGTCCGATCTAGGCGCTGCGGCCCCGCGGTCAGATGCTAG TAGCCCATTTCCA AGCTTGATAGGGTCTCTTACCAGCACTCGCACCACCCGCCCGCGCCTGCTGGGCGAGGAG GAGTACCTAAACA ACTCGCTGCTGCAGCCGCAGCGCGAAAAAAACCTGCCTCCGGCATTTCCCAACAACGGGA TAGAGAGCCTAGT GGACAAGATGAGTAGATGGAAGACGTACGCGCAGGAGCACAGGGACGTGCCAGGCCCGCG CCCGCCCACCCGT CGTCAAAGGCACGACCGTCAGCGGGGTCTGGTGTGGGAGGACGATGACTCGGCAGACGAC AGCAGCGTCCTGG ATTTGGGAGGGAGTGGCAACCCGTTTGCGCACCTTCGCCCCAGGCTGGGGAGAATGTTTT AAAAAAAAAAAAG CAT GAT GC AAAAT AAAAAAC T C ACC AAGGCC AT SEQ ID NO: 4 (pBEL066 Ad 5 wt)

ATTATTATAGTCAGCTGACGTGTAGTGTATTTATACCCGGTGAGTTCCTCAAGAGGCCAC TCTTGAGTGCCAGCGAGTAGAGTTTTCTCCTCCGAGCCGCTCCGACACCGGGACTGAAAA TGAGACATATTATCTGCCACGGAGGTGTTATTACCGAAGAAATGGCCGCCAGTCTTTTGG ACCAGCTGATCGAAGAGGTACTGGCTGATAATCTTCCACCTCCTAGCCATTTTGAACCAC CTACCCTTCACGAACTGTATGATTTAGACGTGACGGCCCCCGAAGATCCCAACGAGGAGG CGGTTTCGCAGATTTTTCCCGACTCTGTAATGTTGGCGGTGCAGGAAGGGATTGACTTAC TCACTTTTCCGCCGGCGCCCGGTTCTCCGGAGCCGCCTCACCTTTCCCGGCAGCCCGAGC AGCCGGAGCAGAGAGCCTTGGGTCCGGTTTCTATGCCAAACCTTGTACCGGAGGTGATCG ATCTTACCTGCCACGAGGCTGGCTTTCCACCCAGTGACGACGAGGATGAAGAGGGTGAGG AGTTTGTGTTAGATTATGTGGAGCACCCCGGGCACGGTTGCAGGTCTTGTCATTATCACC GGAGGAATACGGGGGACCCAGATATTATGTGTTCGCTTTGCTATATGAGGACCTGTGGCA TGTTTGTCTACAGTAAGTGAAAATTATGGGCAGTGGGTGATAGAGTGGTGGGTTTGGTGT GGTAATTTTTTTTTTAATTTTTACAGTTTTGTGGTTTAAAGAATTTTGTATTGTGATTTT TTTAAAAGGTCCTGTGTCTGAACCTGAGCCTGAGCCCGAGCCAGAACCGGAGCCTGCAAG ACCTACCCGCCGTCCTAAAATGGCGCCTGCTATCCTGAGACGCCCGACATCACCTGTGTC TAGAGAATGCAATAGTAGTACGGATAGCTGTGACTCCGGTCCTTCTAACACACCTCCTGA GATACACCCGGTGGTCCCGCTGTGCCCCATTAAACCAGTTGCCGTGAGAGTTGGTGGGCG TCGCCAGGCTGTGGAATGTATCGAGGACTTGCTTAACGAGCCTGGGCAACCTTTGGACTT GAGCTGTAAACGCCCCAGGCCATAAGGTGTAAACCTGTGATTGCGTGTGTGGTTAACGCC TTTGTTTGCTGAATGAGTTGATGTAAGTTTAATAAAGGGTGAGATAATGTTTAACTTGCA TGGCGTGTTAAATGGGGCGGGGCTTAAAGGGTATATAATGCGCCGTGGGCTAATCTTGGT TACATCTGACCTCATGGAGGCTTGGGAGTGTTTGGAAGATTTTTCTGCTGTGCGTAACTT GCTGGAACAGAGCTCTAACAGTACCTCTTGGTTTTGGAGGTTTCTGTGGGGCTCATCCCA GGC AAAGT AGT C T GCAGAA AAGGAGGAT AC AAG GGGAAT T GAAGAGC T T GAA ATCCTGTGGTGAGCTGTTTGATTCTTTGAATCTGGGTCACCAGGCGCTTTTCCAAGAGAA GGTCATCAAGACTTTGGATTTTTCCACACCGGGGCGCGCTGCGGCTGCTGTTGCTTTTTT GAGTTTTATAAAGGATAAATGGAGCGAAGAAACCCATCTGAGCGGGGGGTACCTGCTGGA TTTTCTGGCCATGCATCTGTGGAGAGCGGTTGTGAGACACAAGAATCGCCTGCTACTGTT GTCTTCCGTCCGCCCGGCGATAATACCGACGGAGGAGCAGCAGCAGCAGCAGGAGGAAGC CAGGCGGCGGCGGCAGGAGCAGAGCCCATGGAACCCGAGAGCCGGCCTGGACCCTCGGGA ATGAATGTTGTACAGGTGGCTGAACTGTATCCAGAACTGAGACGCATTTTGACAATTACA GAGGATGGGCAGGGGCTAAAGGGGGTAAAGAGGGAGCGGGGGGCTTGTGAGGCTACAGAG GAGGCTAGGAATCTAGCTTTTAGCTTAATGACCAGACACCGTCCTGAGTGTATTACTTTT CAACAGATCAAGGATAATTGCGCTAATGAGCTTGATCTGCTGGCGCAGAAGTATTCCATA GAGCAGC GACC AC AC GGC GC AGCC AGGGGA GAT T T GAGGAGGC A AGGGTA T AT GC AAAGGT GGC AC T T AGGCC AGAT T GC AAGT AC AAGAT C AGC AAAC T T GT AAAT AT C AGGAATTGTTGCTACATTTCTGGGAACGGGGCCGAGGTGGAGATAGATACGGAGGATAGG GTGGCCTTTAGATGTAGCATGATAAATATGTGGCCGGGGGTGCTTGGCATGGACGGGGTG GTTATTATGAATGTAAGGTTTACTGGCCCCAATTTTAGCGGTACGGTTTTCCTGGCCAAT ACCAACCTTATCCTACACGGTGTAAGCTTCTATGGGTTTAACAATACCTGTGTGGAAGCC TGGACCGATGTAAGGGTTCGGGGCTGTGCCTTTTACTGCTGCTGGAAGGGGGTGGTGTGT CGCCCCAAAAGCAGGGCTTCAATTAAGAAATGCCTCTTTGAAAGGTGTACCTTGGGTATC CTGTCTGAGGGTAACTCCAGGGTGCGCCACAATGTGGCCTCCGACTGTGGTTGCTTCATG CTAGTGAAAAGCGTGGCTGTGATTAAGCATAACATGGTATGTGGCAACTGCGAGGACAGG GCCTCTCAGATGCTGACCTGCTCGGACGGCAACTGTCACCTGCTGAAGACCATTCACGTA GCCAGCCACTCTCGCAAGGCCTGGCCAGTGTTTGAGCATAACATACTGACCCGCTGTTCC TTGCATTTGGGTAACAGGAGGGGGGTGTTCCTACCTTACCAATGCAATTTGAGTCACACT AAGATATTGCTTGAGCCCGAGAGCATGTCCAAGGTGAACCTGAACGGGGTGTTTGACATG ACCATGAAGATCTGGAAGGTGCTGAGGTACGATGAGACCCGCACCAGGTGCAGACCCTGC GAGTGTGGCGGTAAACATATTAGGAACCAGCCTGTGATGCTGGATGTGACCGAGGAGCTG AGGCCCGATCACTTGGTGCTGGCCTGCACCCGCGCTGAGTTTGGCTCTAGCGATGAAGAT ACAGATTGAGGTACTGAAATGTGtgggcgtggCttaagggtgggaaagaatatataaggt gggggtcttatgtagttttgtatctgttttgcagcagccgccgccgccatgagcaccaac tcgtttgatggaagcattgtgagctcatatttgacaacgcgcatgcccccatgggccggg gtgcgtcagaatgtgatgggctccagcattgatggtcgccccgtcctgcccgcaaactct actaccttgacctacgagaccgtgtctggaacgccgttggagactgcagcctccgccgcc gcttcagccgctgcagccaccgcccgcgggattgtgactgactttgctttcctgagcccg cttgcaagcagtgcagcttcccgttcatccgcccgcgatgacaagttgacggctcttttg gcacaattggattctttgacccgggaacttaatgtcgtttctcagcagctgttggatctg cgccagcaggtttctgccctgaaggcttcctcccctcccaatgcggtttaaaacataaat aaaaaaccagactctgtttggatttggatcaagcaagtgtcttgctgtctttatttaggg gttttgcgcgcgcggtaggcccgggaccagcggtctcggtcgttgagggtcctgtgtatt ttttccaggacgtggtaaaggtgactctggatgttcagatacatgggcataagcccgtct ctggggtggaggtagcaccactgcagagcttcatgctgcggggtggtgttgtagatgatc cagtcgtagcaggagcgctgggcgtggtgcctaaaaatgtctttcagtagcaagctgatt gccaggggcaggcccttggtgtaagtgtttacaaagcggttaagctgggatgggtgcata cgtggggatatgagatgcatcttggactgtatttttaggttggctatgttcccagccata tccctccggggattcatgttgtgcagaaccaccagcacagtgtatccggtgcacttggga aatttgtcatgtagcttagaaggaaatgcgtggaagaacttggagacgcccttgtgacct ccaagattttccatgcattcgtccataatgatggcaatgggcccacgggcggcggcctgg gcgaagatatttctgggatcactaacgtcatagttgtgttccaggatgagatcgtcatag gccatttttacaaagcgcgggcggagggtgccagactgcggtataatggttccatccggc ccaggggcgtagttaccctcacagatttgcatttcccacgctttgagttcagatgggggg atcatgtctacctgcggggcgatgaagaaaacggtttccggggtaggggagatcagctgg gaagaaagcaggttcctgagcagctgcgacttaccgcagccggtgggcccgtaaatcaca cctattaccgggtgcaactggtagttaagagagctgcagctgccgtcatccctgagcagg ggggccacttcgttaagcatgtccctgactcgcatgttttccctgaccaaatccgccaga aggcgctcgccgcccagcgatagcagttcttgcaaggaagcaaagtttttcaacggtttg agaccgtccgccgtaggcatgcttttgagcgtttgaccaagcagttccaggcggtcccac agctcggtcacctgctctacggcatctcgatccagcatatctcctcgtttcgcgggttgg ggcggctttcgctgtacggcagtagtcggtgctcgtccagacgggccagggtcatgtctt tccacgggcgcagggtcctcgtcagcgtagtctgggtcacggtgaaggggtgcgctccgg gctgcgcgctggccagggtgcgcttgaggctggtcctgctggtgctgaagcgctgccggt cttcgccctgcgcgtcggccaggtagcatttgaccatggtgtcatagtccagcccctccg cggcgtggcccttggcgcgcagcttgcccttggaggaggcgccgcacgaggggcagtgca gacttttgagggcgtagagcttgggcgcgagaaataccgattccggggagtaggcatccg cgccgcaggccccgcagacggtctcgcattccacgagccaggtgagctctggccgttcgg ggtcaaaaaccaggtttcccccatgctttttgatgcgtttcttacctctggtttccatga gccggtgtccacgctcggtgacgaaaaggctgtccgtgtccccgtatacagacttgagag gcctgtcctcgagcggtgttccgcggtcctcctcgtatagaaactcggaccactctgaga caaaggctcgcgtccaggccagcacgaaggaggctaagtgggaggggtagcggtcgttgt ccactagggggtccactcgctccagggtgtgaagacacatgtcgccctcttcggcatcaa ggaaggtgattggtttgtaggtgtaggccacgtgaccgggtgttcctgaaggggggctat aaaagggggtgggggcgcgttcgtcctcactctcttccgcatcgctgtctgcgagggcca gctgttggggtgagtactccctctgaaaagcgggcatgacttctgcgctaagattgtcag tttccaaaaacgaggaggatttgatattcacctggcccgcggtgatgcctttgagggtgg ccgcatccatctggtcagaaaagacaatctttttgttgtcaagcttggtggcaaacgacc cgtagagggcgttggacagcaacttggcgatggagcgcagggtttggtttttgtcgcgat cggcgcgctccttggccgcgatgtttagctgcacgtattcgcgcgcaacgcaccgccatt cgggaaagacggtggtgcgctcgtcgggcaccaggtgcacgcgccaaccgcggttgtgca gggtgacaaggtcaacgctggtggctacctctccgcgtaggcgctcgttggtccagcaga ggcggccgcccttgcgcgagcagaatggcggtagggggtctagctgcgtctcgtccgggg ggtctgcgtccacggtaaagaccccgggcagcaggcgcgcgtcgaagtagtctatcttgc atccttgcaagtctagcgcctgctgccatgcgcgggcggcaagcgcgcgctcgtatgggt tgagtgggggaccccatggcatggggtgggtgagcgcggaggcgtacatgccgcaaatgt cgtaaacgtagaggggctctctgagtattccaagatatgtagggtagcatcttccaccgc ggatgctggcgcgcacgtaatcgtatagttcgtgcgagggagcgaggaggtcgggaccga ggttgctacgggcgggctgctctgctcggaagactatctgcctgaagatggcatgtgagt tggatgatatggttggacgctggaagacgttgaagctggcgtctgtgagacctaccgcgt cacgcacgaaggaggcgtaggagtcgcgcagcttgttgaccagctcggcggtgacctgca cgtctagggcgcagtagtccagggtttccttgatgatgtcatacttatcctgtccctttt ttttccacagctcgcggttgaggacaaactcttcgcggtctttccagtactcttggatcg gaaacccgtcggcctccgaacggtaagagcctagcatgtagaactggttgacggcctggt aggcgcagcatcccttttctacgggtagcgcgtatgcctgcgcggccttccggagcgagg tgtgggtgagcgcaaaggtgtccctgaccatgactttgaggtactggtatttgaagtcag tgtcgtcgcatccgccctgctcccagagcaaaaagtccgtgcgctttttggaacgcggat ttggcagggcgaaggtgacatcgttgaagagtatctttcccgcgcgaggcataaagttgc gtgtgatgcggaagggtcccggcacctcggaacggttgttaattacctgggcggcgagca cgatctcgtcaaagccgttgatgttgtggcccacaatgtaaagttccaagaagcgcggga tgcccttgatggaaggcaattttttaagttcctcgtaggtgagctcttcaggggagctga gcccgtgctctgaaagggcccagtctgcaagatgagggttggaagcgacgaatgagctcc acaggtcacgggccattagcatttgcaggtggtcgcgaaaggtcctaaactggcgaccta tggccattttttctggggtgatgcagtagaaggtaagcgggtcttgttcccagcggtccc atccaaggttcgcggctaggtctcgcgcggcagtcactagaggctcatctccgccgaact tcatgaccagcatgaagggcacgagctgcttcccaaaggcccccatccaagtataggtct ctacatcgtaggtgacaaagagacgctcggtgcgaggatgcgagccgatcgggaagaact ggatctcccgccaccaattggaggagtggctattgatgtggtgaaagtagaagtccctgc gacgggccgaacactcgtgctggcttttgtaaaaacgtgcgcagtactggcagcggtgca cgggctgtacatcctgcacgaggttgacctgacgaccgcgcacaaggaagcagagtggga atttgagcccctcgcctggcgggtttggctggtggtcttctacttcggctgcttgtcctt gaccgtctggctgctcgaggggagttacggtggatcggaccaccacgccgcgcgagccca aagtccagatgtccgcgcgcggcggtcggagcttgatgacaacatcgcgcagatgggagc tgtccatggtctggagctcccgcggcgtcaggtcaggcgggagctcctgcaggtttacct cgcatagacgggtcagggcgcgggctagatccaggtgatacctaatttccaggggctggt tggtggcggcgtcgatggcttgcaagaggccgcatccccgcggcgcgactacggtaccgc gcggcgggcggtgggccgcgggggtgtccttggatgatgcatctaaaagcggtgacgcgg gcgagcccccggaggtagggggggctccggacccgccgggagagggggcaggggcacgtc ggcgccgcgcgcgggcaggagctggtgctgcgcgcgtaggttgctggcgaacgcgacgac gcggcggttgatctcctgaatctggcgcctctgcgtgaagacgacgggcccggtgagctt gagcctgaaagagagttcgacagaatcaatttcggtgtcgttgacggcggcctggcgcaa aatctcctgcacgtctcctgagttgtcttgataggcgatctcggccatgaactgctcgat ctcttcctcctggagatctccgcgtccggctcgctccacggtggcggcgaggtcgttgga aatgcgggccatgagctgcgagaaggcgttgaggcctccctcgttccagacgcggctgta gaccacgcccccttcggcatcgcgggcgcgcatgaccacctgcgcgagattgagctccac gtgccgggcgaagacggcgtagtttcgcaggcgctgaaagaggtagttgagggtggtggc ggtgtgttctgccacgaagaagtacataacccagcgtcgcaacgtggattcgttgatatc ccccaaggcctcaaggcgctccatggcctcgtagaagtccacggcgaagttgaaaaactg ggagttgcgcgccgacacggttaactcctcctccagaagacggatgagctcggcgacagt gtcgcgcacctcgcgctcaaaggctacaggggcctcttcttcttcttcaatctcctcttc cataagggcctccccttcttcttcttctggcggcggtgggggaggggggacacggcggcg acgacggcgcaccgggaggcggtcgacaaagcgctcgatcatctccccgcggcgacggcg catggtctcggtgacggcgcggccgttctcgcgggggcgcagttggaagacgccgcccgt catgtcccggttatgggttggcggggggctgccatgcggcagggatacggcgctaacgat gcatctcaacaattgttgtgtaggtactccgccgccgagggacctgagcgagtccgcatc gaccggatcggaaaacctctcgagaaaggcgtctaaccagtcacagtcgcaaggtaggct gagcaccgtggcgggcggcagcgggcggcggtcggggttgtttctggcggaggtgctgct gatgatgtaattaaagtaggcggtcttgagacggcggatggtcgacagaagcaccatgtc cttgggtccggcctgctgaatgcgcaggcggtcggccatgccccaggcttcgttttgaca tcggcgcaggtctttgtagtagtcttgcatgagcctttctaccggcacttcttcttctcc ttcctcttgtcctgcatctcttgcatctatcgctgcggcggcggcggagtttggccgtag gtggcgccctcttcctcccatgcgtgtgaccccgaagcccctcatcggctgaagcagggc taggtcggcgacaacgcgctcggctaatatggcctgctgcacctgcgtgagggtagactg gaagtcatccatgtccacaaagcggtggtatgcgcccgtgttgatggtgtaagtgcagtt ggccataacggaccagttaacggtctggtgacccggctgcgagagctcggtgtacctgag acgcgagtaagccctcgagtcaaatacgtagtcgttgcaagtccgcaccaggtactggta tcccaccaaaaagtgcggcggcggctggcggtagaggggccagcgtagggtggccggggc tccgggggcgagatcttccaacataaggcgatgatatccgtagatgtacctggacatcca ggtgatgccggcggcggtggtggaggcgcgcggaaagtcgcggacgcggttccagatgtt gcgcagcggcaaaaagtgctccatggtcgggacgctctggccggtcaggcgcgcgcaatc gttgacgctctagaccgtgcaaaaggagagcctgtaagcgggcactcttccgtggtctgg tggataaattcgcaagggtatcatggcggacgaccggggttcgagccccgtatccggccg tccgccgtgatccatgcggttaccgcccgcgtgtcgaacccaggtgtgcgacgtcagaca acgggggagtgctccttttggcttccttccaggcgcggcggctgctgcgctagctttttt ggccactggccgcgcgcagcgtaagcggttaggctggaaagcgaaagcattaagtggctc gctccctgtagccggagggttattttccaagggttgagtcgcgggacccccggttcgagt ctcggaccggccggactgcggcgaacgggggtttgcctccccgtcatgcaagaccccgct tgcaaattcctccggaaacagggacgagccccttttttgcttttcccagatgcatccggt gctgcggcagatgcgcccccctcctcagcagcggcaagagcaagagcagcggcagacatg cagggcaccctcccctcctcctaccgcgtcaggaggggcgacatccgcggttgacgcggc agcagatggtgattacgaacccccgcggcgccgggcccggcactacctggacttggagga gggcgagggcctggcgcggctaggagcgccctctcctgagcggtacccaagggtgcagct gaagcgtgatacgcgtgaggcgtacgtgccgcggcagaacctgtttcgcgaccgcgaggg agaggagcccgaggagatgcgggatcgaaagttccacgcagggcgcgagctgcggcatgg cctgaatcgcgagcggttgctgcgcgaggaggactttgagcccgacgcgcgaaccgggat tagtccccgtggcggccgccgacctggtaaccgcatacgagcagacggtgaaccaggaga ttaactttcaagcgcgcgcacaaaaagctttaacaaccacgtgcgtacgcttgtggcgcg cgaggaggtggctataggactgatgcatctgtgggactttgtaagcgcgctggagcaaaa cccaaatagcaagccgctcatggcgcagctgttccttatagtgcagcacagcagggacaa cgaggcattcagggatgcgctgctaaacatagtagagcccgagggccgctggctgctcga tttgataaacatcctgcagagcatagtggtgcaggagcgcagcttgagcctggctgacaa ggtggccgccatcaactattccatgcttagcctgggcaagttttacgcccgcaagatata ccataccccttacgttcccatagacaaggaggtaaagatcgaggggttctacatgcgcat ggcgctgaaggtgcttaccttgagcgacgacctgggcgtttatcgcaacgagcgcatcca caaggccgtgagcgtgagccggcggcgcgagctcagcgaccgcgagctgatgcacagcct gcaaagggccctggctggcacgggcagcggcgatagagaggccgagtcctactttgacgc gggcgctgacctgcgctgggccccaagccgacgcgccctggaggcagctggggccggacc tgggctggcggtggcacccgcgcgcgctggcaacgtcggcggcgtggaggaatatgacga ggacgatgagtacgagccagaggacggcgagtactaagcggtgatgtttctgatcagatg atgcaagacgcaacggacccggcggtgcgggcggcgctgcagagccagccgtccggcctt aactccacggacgactggcgccaggtcatggaccgcatcatgtcgctgactgcgcgcaat cctgacgcgttccggcagcagccgcaggccaaccggctctccgcaattctggaagcggtg gtcccggcgcgcgcaaaccccacgcacgagaaggtgctggcgatcgtaaacgcgctggcc gaaaacagggccatccggcccgacgaggccggcctggtctacgacgcgctgcttcagcgc gtggctcgttacaacagcggcaacgtgcagaccaacctggaccggctggtgggggatgtg cgcgaggccgtggcgcagcgtgagcgcgcgcagcagcagggcaacctgggctccatggtt gcactaaacgccttcctgagtacacagcccgccaacgtgccgcggggacaggaggactac accaactttgtgagcgcactgcggctaatggtgactgagacaccgcaaagtgaggtgtac cagtctgggccagactattttttccagaccagtagacaaggcctgcagaccgtaaacctg agccaggctttcaaaaacttgcaggggctgtggggggtgcgggctcccacaggcgaccgc gcgaccgtgtctagcttgctgacgcccaactcgcgcctgttgctgctgctaatagcgccc ttcacggacagtggcagcgtgtcccgggacacatacctaggtcacttgctgacactgtac cgcgaggccataggtcaggcgcatgtggacgagcatactttccaggagattacaagtgtc agccgcgcgctggggcaggaggacacgggcagcctggaggcaaccctaaactacctgctg accaaccggcggcagaagatcccctcgttgcacagtttaaacagcgaggaggagcgcatt ttgcgctacgtgcagcagagcgtgagccttaacctgatgcgcgacggggtaacgcccagc gtggcgctggacatgaccgcgcgcaacatggaaccgggcatgtatgcctcaaaccggccg tttatcaaccgcctaatggactacttgcatcgcgcggccgccgtgaaccccgagtatttc accaatgccatcttgaacccgcactggctaccgccccctggtttctacaccgggggattc gaggtgcccgagggtaacgatggattcctctgggacgacatagacgacagcgtgttttcc ccgcaaccgcagaccctgctagagttgcaacagcgcgagcaggcagaggcggcgctgcga aaggaaagcttccgcaggccaagcagcttgtccgatctaggcgctgcggccccgcggtca gatgctagtagcccatttccaagcttgatagggtctcttaccagcactcgcaccacccgc ccgcgcctgctgggcgaggaggagtacctaaacaactcgctgctgcagccgcagcgcgaa aaaaacctgcctccggcatttcccaacaacgggatagagagcctagtggacaagatgagt agatggaagacgtacgcgcaggagcacagggacgtgccaggcccgcgcccgcccacccgt cgtcaaaggcacgaccgtcagcggggtctggtgtgggaggacgatgactcggcagacgac agcagcgtcctggatttgggagggagtggcaacccgtttgcgcaccttcgccccaggctg gggagaatgttttaaaaaaaaaaaagcatgatgcaaaataaaaaactcaccaaggccatg gcaccgagcgttggttttcttgtattccccttagtatgcggcgcgcggcgatgtatgagg aaggtcctcctccctcctacgagagtgtggtgagcgcggcgccagtggcggcggcgctgg gttctcccttcgatgctcccctggacccgccgtttgtgcctccgcggtacctgcggccta ccggggggagaaacagcatccgttactctgagttggcacccctattcgacaccacccgtg tgtacctggtggacaacaagtcaacggatgtggcatccctgaactaccagaacgaccaca gcaactttctgaccacggtcattcaaaacaatgactacagcccgggggaggcaagcacac agaccatcaatcttgacgaccggtcgcactggggcggcgacctgaaaaccatcctgcata ccaacatgccaaatgtgaacgagttcatgtttaccaataagtttaaggcgcgggtgatgg tgtcgcgcttgcctactaaggacaatcaggtggagctgaaatacgagtgggtggagttca cgctgcccgagggcaactactccgagaccatgaccatagaccttatgaacaacgcgatcg tggagcactacttgaaagtgggcagacagaacggggttctggaaagcgacatcggggtaa agtttgacacccgcaacttcagactggggtttgaccccgtcactggtcttgtcatgcctg gggtatatacaaacgaagccttccatccagacatcattttgctgccaggatgcggggtgg acttcacccacagccgcctgagcaacttgttgggcatccgcaagcggcaacccttccagg agggctttaggatcacctacgatgatctggagggtggtaacattcccgcactgttggatg tggacgcctaccaggcgagcttgaaagatgacaccgaacagggcgggggtggcgcaggcg gcagcaacagcagtggcagcggcgcggaagagaactccaacgcggcagccgcggcaatgc agccggtggaggacatgaacgatcatgccattcgcggcgacacctttgccacacgggctg aggagaagcgcgctgaggccgaagcagcggccgaagctgccgcccccgctgcgcaacccg aggtcgagaagcctcagaagaaaccggtgatcaaacccctgacagaggacagcaagaaac gcagttacaacctaataagcaatgacagcaccttcacccagtaccgcagctggtaccttg catacaactacggcgaccctcagaccggaatccgctcatggaccctgctttgcactcctg acgtaacctgcggctcggagcaggtctactggtcgttgccagacatgatgcaagaccccg tgaccttccgctccacgcgccagatcagcaactttccggtggtgggcgccgagctgttgc ccgtgcactccaagagcttctacaacgaccaggccgtctactcccaactcatccgccagt ttacctctctgacccacgtgttcaatcgctttcccgagaaccagattttggcgcgcccgc cagcccccaccatcaccaccgtcagtgaaaacgttcctgctctcacagatcacgggacgc taccgctgcgcaacagcatcggaggagtccagcgagtgaccattactgacgccagacgcc gcacctgcccctacgtttacaaggccctgggcatagtctcgccgcgcgtcctatcgagcc gcactttttgagcaagcatgtccatccttatatcgcccagcaataacacaggctggggcc tgcgcttcccaagcaagatgtttggcggggccaagaagcgctccgaccaacacccagtgc gcgtgcgcgggcactaccgcgcgccctggggcgcgcacaaacgcggccgcactgggcgca ccaccgtcgatgacgccatcgacgcggtggtggaggaggcgcgcaactacacgcccacgc cgccaccagtgtccacagtggacgcggccattcagaccgtggtgcgcggagcccggcgct atgctaaaatgaagagacggcggaggcgcgtagcacgtcgccaccgccgccgacccggca ctgccgcccaacgcgcggcggcggccctgcttaaccgcgcacgtcgcaccggccgacggg cggccatgcgggccgctcgaaggctggccgcgggtattgtcactgtgccccccaggtcca ggcgacgagcggccgccgcagcagccgcggccattagtgctatgactcagggtcgcaggg gcaacgtgtattgggtgcgcgactcggttagcggcctgcgcgtgcccgtgcgcacccgcc ccccgcgcaactagattgcaagaaaaaactacttagactcgtactgttgtatgtatccag cggcggcggcgcgcaacgaagctatgtccaagcgcaaaatcaaagaagagatgctccagg tcatcgcgccggagatctatggccccccgaagaaggaagagcaggattacaagccccgaa agctaaagcgggtcaaaaagaaaaagaaagatgatgatgatgaacttgacgacgaggtgg aactgctgcacgctaccgcgcccaggcgacgggtacagtggaaaggtcgacgcgtaaaac gtgttttgcgacccggcaccaccgtagtctttacgcccggtgagcgctccacccgcacct acaagcgcgtgtatgatgaggtgtacggcgacgaggacctgcttgagcaggccaacgagc gcctcggggagtttgcctacggaaagcggcataaggacatgctggcgttgccgctggacg agggcaacccaacacctagcctaaagcccgtaacactgcagcaggtgctgcccgcgcttg caccgtccgaagaaaagcgcggcctaaagcgcgagtctggtgacttggcacccaccgtgc agctgatggtacccaagcgccagcgactggaagatgtcttggaaaaaatgaccgtggaac ctgggctggagcccgaggtccgcgtgcggccaatcaagcaggtggcgccgggactgggcg tgcagaccgtggacgttcagatacccactaccagtagcaccagtattgccaccgccacag agggcatggagacacaaacgtccccggttgcctcagcggtggcggatgccgcggtgcagg cggtcgctgcggccgcgtccaagacctctacggaggtgcaaacggacccgtggatgtttc gcgtttcagccccccggcgcccgcgcggttcgaggaagtacggcgccgccagcgcgctac tgcccgaatatgccctacatccttccattgcgcctacccccggctatcgtggctacacct accgccccagaagacgagcaactacccgacgccgaaccaccactggaacccgccgccgcc gtcgccgtcgccagcccgtgctggccccgatttccgtgcgcagggtggctcgcgaaggag gcaggaccctggtgctgccaacagcgcgctaccaccccagcatcgtttaaaagccggtct ttgtggttcttgcagatatggccctcacctgccgcctccgtttcccggtgccgggattcc gaggaagaatgcaccgtaggaggggcatggccggccacggcctgacgggcggcatgcgtc gtgcgcaccaccggcggcggcgcgcgtcgcaccgtcgcatgcgcggcggtatcctgcccc tccttattccactgatcgccgcggcgattggcgccgtgcccggaattgcatccgtggcct tgcaggcgcagagacactgattaaaaacaagttgcatgtggaaaaatcaaaataaaaagt ctggactctcacgctcgcttggtcctgtaactattttgtagaatggaagacatcaacttt gcgtctctggccccgcgacacggctcgcgcccgttcatgggaaactggcaagatatcggc accagcaatatgagcggtggcgccttcagctggggctcgctgtggagcggcattaaaaat ttcggttccaccgttaagaactatggcagcaaggcctggaacagcagcacaggccagatg ctgagggataagttgaaagagcaaaatttccaacaaaaggtggtagatggcctggcctct ggcattagcggggtggtggacctggccaaccaggcagtgcaaaataagattaacagtaag cttgatccccgccctcccgtagaggagcctccaccggccgtggagacagtgtctccagag gggcgtggcgaaaagcgtccgcgccccgacagggaagaaactctggtgacgcaaatagac gagcctccctcgtacgaggaggcactaaagcaaggcctgcccaccacccgtcccatcgcg cccatggctaccggagtgctgggccagcacacacccgtaacgctggacctgcctcccccc gccgacacccagcagaaacctgtgctgccaggcccgaccgccgttgttgtaacccgtcct agccgcgcgtccctgcgccgcgccgccagcggtccgcgatcgttgcggcccgtagccagt ggcaactggcaaagcacactgaacagcatcgtgggtctgggggtgcaatccctgaagcgc cgacgatgcttctgaatagctaacgtgtcgtatgtgtgtcatgtatgcgtccatgtcgcc gccagaggagctgctgagccgccgcgcgcccgctttccaagatggctaccccttcgatga tgccgcagtggtcttacatgcacatctcgggccaggacgcctcggagtacctgagccccg ggctggtgcagtttgcccgcgccaccgagacgtacttcagcctgaataacaagtttagaa accccacggtggcgcctacgcacgacgtgaccacagaccggtcccagcgtttgacgctgc ggttcatccctgtggaccgtgaggatactgcgtactcgtacaaggcgcggttcaccctag ctgtgggtgataaccgtgtgctggacatggcttccacgtactttgacatccgcggcgtgc tggacaggggccctacttttaagccctactctggcactgcctacaacgccctggctccca agggtgccccaaatccttgcgaatgggatgaagctgctactgctcttgaaataaacctag aagaagaggacgatgacaacgaagacgaagtagacgagcaagctgagcagcaaaaaactc acgtatttgggcaggcgccttattctggtataaatattacaaaggagggtattcaaatag gtgtcgaaggtcaaacacctaaatatgccgataaaacatttcaacctgaacctcaaatag gagaatctcagtggtacgaaactgaaattaatcatgcagctgggagagtccttaaaaaga ctaccccaatgaaaccatgttacggttcatatgcaaaacccacaaatgaaaatggagggc aaggcattcttgtaaagcaacaaaatggaaagctagaaagtcaagtggaaatgcaatttt tctcaactactgaggcgaccgcaggcaatggtgataacttgactcctaaagtggtattgt acagtgaagatgtagatatagaaaccccagacactcatatttcttacatgcccactatta aggaaggtaactcacgagaactaatgggccaacaatctatgcccaacaggcctaattaca ttgcttttagggacaattttattggtctaatgtattacaacagcacgggtaatatgggtg ttctggcgggccaagcatcgcagttgaatgctgttgtagatttgcaagacagaaacacag agctttcataccagcttttgcttgattccattggtgatagaaccaggtacttttctatgt ggaatcaggctgttgacagctatgatccagatgttagaattattgaaaatcatggaactg aagatgaacttccaaattactgctttccactgggaggtgtgattaatacagagactctta ccaaggtaaaacctaaaacaggtcaggaaaatggatgggaaaaagatgctacagaatttt cagataaaaatgaaataagagttggaaataattttgccatggaaatcaatctaaatgcca acctgtggagaaatttcctgtactccaacatagcgctgtatttgcccgacaagctaaagt acagtccttccaacgtaaaaatttctgataacccaaacacctacgactacatgaacaagc gagtggtggctcccgggttagtggactgctacattaaccttggagcacgctggtcccttg actatatggacaacgtcaacccatttaaccaccaccgcaatgctggcctgcgctaccgct caatgttgctgggcaatggtcgctatgtgcccttccacatccaggtgcctcagaagttct ttgccattaaaaacctccttctcctgccgggctcatacacctacgagtggaacttcagga aggatgttaacatggttctgcagagctccctaggaaatgacctaagggttgacggagcca gcattaagtttgatagcatttgcctttacgccaccttcttccccatggcccacaacaccg cctccacgcttgaggccatgcttagaaacgacaccaacgaccagtcctttaacgactatc tctccgccgccaacatgctctaccctatacccgccaacgctaccaacgtgcccatatcca tcccctcccgcaactgggcggctttccgcggctgggccttcacgcgccttaagactaagg aaaccccatcactgggctcgggctacgacccttattacacctactctggctctataccct acctagatggaaccttttacctcaaccacacctttaagaaggtggccattacctttgact cttctgtcagctggcctggcaatgaccgcctgcttacccccaacgagtttgaaattaagc gctcagttgacggggagggttacaacgttgcccagtgtaacatgaccaaagactggttcc tggtacaaatgctagctaactacaacattggctaccagggcttctatatcccagagagct acaaggaccgcatgtactccttctttagaaacttccagcccatgagccgtcaggtggtgg atgatactaaatacaaggactaccaacaggtgggcatcctacaccaacacaacaactctg gatttgttggctaccttgcccccaccatgcgcgaaggacaggcctaccctgctaacttcc cctatccgcttataggcaagaccgcagttgacagcattacccagaaaaagtttctttgcg atcgcaccctttggcgcatcccattctccagtaactttatgtccatgggcgcactcacag acctgggccaaaaccttctctacgccaactccgcccacgcgctagacatgacttttgagg tggatcccatggacgagcccacccttctttatgttttgtttgaagtctttgacgtggtcc gtgtgcaccggccgcaccgcggcgtcatcgaaaccgtgtacctgcgcacgcccttctcgg ccggcaacgccacaacataaagaagcaagcaacatcaacaacagctgccgccatgggctc cagtgagcaggaactgaaagccattgtcaaagatcttggttgtgggccatattttttggg cacctatgacaagcgctttccaggctttgtttctccacacaagctcgcctgcgccatagt caatacggccggtcgcgagactgggggcgtacactggatggcctttgcctggaacccgca ctcaaaaacatgctacctctttgagccctttggcttttctgaccagcgactcaagcaggt ttaccagtttgagtacgagtcactcctgcgccgtagcgccattgcttcttcccccgaccg ctgtataacgctggaaaagtccacccaaagcgtacaggggcccaactcggccgcctgtgg actattctgctgcatgtttctccacgcctttgccaactggccccaaactcccatggatca caaccccaccatgaaccttattaccggggtacccaactccatgctcaacagtccccaggt acagcccaccctgcgtcgcaaccaggaacagctctacagcttcctggagcgccactcgcc ctacttccgcagccacagtgcgcagattaggagcgccacttctttttgtcacttgaaaaa catgtaaaaataatgtactagagacactttcaataaaggcaaatgcttttatttgtacac tctcgggtgattatttacccccacccttgccgtctgcgccgtttaaaaatcaaaggggtt ctgccgcgcatcgctatgcgccactggcagggacacgttgcgatactggtgtttagtgct ccacttaaactcaggcacaaccatccgcggcagctcggtgaagttttcactccacaggct gcgcaccatcaccaacgcgtttagcaggtcgggcgccgatatcttgaagtcgcagttggg gcctccgccctgcgcgcgcgagttgcgatacacagggttgcagcactggaacactatcag cgccgggtggtgcacgctggccagcacgctcttgtcggagatcagatccgcgtccaggtc ctccgcgttgctcagggcgaacggagtcaactttggtagctgccttcccaaaaagggcgc gtgcccaggctttgagttgcactcgcaccgtagtggcatcaaaaggtgaccgtgcccggt ctgggcgttaggatacagcgcctgcataaaagccttgatctgcttaaaagccacctgagc ctttgcgccttcagagaagaacatgccgcaagacttgccggaaaactgattggccggaca ggccgcgtcgtgcacgcagcaccttgcgtcggtgttggagatctgcaccacatttcggcc ccaccggttcttcacgatcttggccttgctagactgctccttcagcgcgcgctgcccgtt ttcgctcgtcacatccatttcaatcacgtgctccttatttatcataatgcttccgtgtag acacttaagctcgccttcgatctcagcgcagcggtgcagccacaacgcgcagcccgtggg ctcgtgatgcttgtaggtcacctctgcaaacgactgcaggtacgcctgcaggaatcgccc catcatcgtcacaaaggtcttgttgctggtgaaggtcagctgcaacccgcggtgctcctc gttcagccaggtcttgcatacggccgccagagcttccacttggtcaggcagtagtttgaa gttcgcctttagatcgttatccacgtggtacttgtccatcagcgcgcgcgcagcctccat gcccttctcccacgcagacacgatcggcacactcagcgggttcatcaccgtaatttcact ttccgcttcgctgggctcttcctcttcctcttgcgtccgcataccacgcgccactgggtc gtcttcattcagccgccgcactgtgcgcttacctcctttgccatgcttgattagcaccgg tgggttgctgaaacccaccatttgtagcgccacatcttctctttcttcctcgctgtccac gattacctctggtgatggcgggcgctcgggcttgggagaagggcgcttctttttcttctt gggcgcaatggccaaatccgccgccgaggtcgatggccgcgggctgggtgtgcgcggcac cagcgcgtcttgtgatgagtcttcctcgtcctcggactcgatacgccgcctcatccgctt ttttgggggcgcccggggaggcggcggcgacggggacggggacgacacgtcctccatggt tgggggacgtcgcgccgcaccgcgtccgcgctcgggggtggtttcgcgctgctcctcttc ccgactggccatttccttctcctataggcagaaaaagatcatggagtcagtcgagaagaa ggacagcctaaccgccccctctgagttcgccaccaccgcctccaccgatgccgccaacgc gcctaccaccttccccgtcgaggcacccccgcttgaggaggaggaagtgattatcgagca ggacccaggttttgtaagcgaagacgacgaggaccgctcagtaccaacagaggataaaaa gcaagaccaggacaacgcagaggcaaacgaggaacaagtcgggcggggggacgaaaggca tggcgactacctagatgtgggagacgacgtgctgttgaagcatctgcagcgccagtgcgc cattatctgcgacgcgttgcaagagcgcagcgatgtgcccctcgccatagcggatgtcag ccttgcctacgaacgccacctattctcaccgcgcgtaccccccaaacgccaagaaaacgg cacatgcgagcccaacccgcgcctcaacttctaccccgtatttgccgtgccagaggtgct tgccacctatcacatctttttccaaaactgcaagatacccctatcctgccgtgccaaccg cagccgagcggacaagcagctggccttgcggcagggcgctgtcatacctgatatcgcctc gctcaacgaagtgccaaaaatctttgagggtcttggacgcgacgagaagcgcgcggcaaa cgctctgcaacaggaaaacagcgaaaatgaaagtcactctggagtgttggtggaactcga gggtgacaacgcgcgcctagccgtactaaaacgcagcatcgaggtcacccactttgccta cccggcacttaacctaccccccaaggtcatgagcacagtcatgagtgagctgatcgtgcg ccgtgcgcagcccctggagagggatgcaaatttgcaagaacaaacagaggagggcctacc cgcagttggcgacgagcagctagcgcgctggcttcaaacgcgcgagcctgccgacttgga ggagcgacgcaaactaatgatggccgcagtgctcgttaccgtggagcttgagtgcatgca gcggttctttgctgacccggagatgcagcgcaagctagaggaaacattgcactacacctt tcgacagggctacgtacgccaggcctgcaagatctccaacgtggagctctgcaacctggt ctcctaccttggaattttgcacgaaaaccgccttgggcaaaacgtgcttcattccacgct caagggcgaggcgcgccgcgactacgtccgcgactgcgtttacttatttctatgctacac ctggcagacggccatgggcgtttggcagcagtgcttggaggagtgcaacctcaaggagct gcagaaactgctaaagcaaaacttgaaggacctatggacggccttcaacgagcgctccgt ggccgcgcacctggcggacatcattttccccgaacgcctgcttaaaaccctgcaacaggg tctgccagacttcaccagtcaaagcatgttgcagaactttaggaactttatcctagagcg ctcaggaatcttgcccgccacctgctgtgcacttcctagcgactttgtgcccattaagta ccgcgaatgccctccgccgctttggggccactgctaccttctgcagctagccaactacct tgcctaccactctgacataatggaagacgtgagcggtgacggtctactggagtgtcactg tcgctgcaacctatgcaccccgcaccgctccctggtttgcaattcgcagctgcttaacga aagtcaaattatcggtacctttgagctgcagggtccctcgcctgacgaaaagtccgcggc tccggggttgaaactcactccggggctgtggacgtcggcttaccttcgcaaatttgtacc tgaggactaccacgcccacgagattaggttctacgaagaccaatcccgcccgccaaatgc ggagcttaccgcctgcgtcattacccagggccacattcttggccaattgcaagccatcaa caaagcccgccaagagtttctgctacgaaagggacggggggtttacttggacccccagtc cggcgaggagctcaacccaatccccccgccgccgcagccctatcagcagcagccgcgggc ccttgcttcccaggatggcacccaaaaagaagctgcagctgccgccgccacccacggacg aggaggaatactgggacagtcaggcagaggaggttttggacgaggaggaggaggacatga tggaagactgggagagcctagacgaggaagcttccgaggtcgaagaggtgtcagacgaaa caccgtcaccctcggtcgcattcccctcgccggcgccccagaaatcggcaaccggttcca gcatggctacaacctccgctcctcaggcgccgccggcactgcccgttcgccgacccaacc gtagatgggacaccactggaaccagggccggtaagtccaagcagccgccgccgttagccc aagagcaacaacagcgccaaggctaccgctcatggcgcgggcacaagaacgccatagttg cttgcttgcaagactgtgggggcaacatctccttcgcccgccgctttcttctctaccatc acggcgtggccttcccccgtaacatcctgcattactaccgtcatctctacagcccatact gcaccggcggcagcggcagcggcagcaacagcagcggccacacagaagcaaaggcgaccg gatagcaagactctgacaaagcccaagaaatccacagcggcggcagcagcaggaggagga gcgctgcgtctggcgcccaacgaacccgtatcgacccgcgagcttagaaacaggattttt cccactctgtatgctatatttcaacagagcaggggccaagaacaagagctgaaaataaaa aacaggtctctgcgatccctcacccgcagctgcctgtatcacaaaagcgaagatcagctt cggcgcacgctggaagacgcggaggctctcttcagtaaatactgcgcgctgactcttaag gactagtttcgcgccctttctcaaatttaagcgcgaaaactacgtcatctccagcggcca cacccggcgccagcacctgtcgtcagcgccattatgagcaaggaaattcccacgccctac atgtggagttaccagccacaaatgggacttgcggctggagctgcccaagactactcaacc cgaataaactacatgagcgcgggaccccacatgatatcccgggtcaacggaatccgcgcc caccgaaaccgaattctcttggaacaggcggctattaccaccacacctcgtaataacctt aatccccgtagttggcccgctgccctggtgtaccaggaaagtcccgctcccaccactgtg gtacttcccagagacgcccaggccgaagttcagatgactaactcaggggcgcagcttgcg ggcggctttcgtcacagggtgcggtcgcccgggcagggtataactcacctgacaatcaga gggcgaggtattcagctcaacgacgagtcggtgagctcctcgcttggtctccgtccggac gggacatttcagatcggcggcgccggccgtccttcattcacgcctcgtcaggcaatccta actctgcagacctcgtcctctgagccgcgctctggaggcattggaactctgcaatttatt gaggagtttgtgccatcggtctactttaaccccttctcgggacctcccggccactatccg gatcaatttattcctaactttgacgcggtaaaggactcggcggacggctacgactgaatg ttaagtggagaggcagagcaactgcgcctgaaacacctggtccactgtcgccgccacaag tgctttgcccgcgactccggtgagttttgctactttgaattgcccgaggatcatatcgag ggcccggcgcacggcgtccggcttaccgcccagggagagcttgcccgtagcctgattcgg gagtttacccagcgccccctgctagttgagcgggacaggggaccctgtgttctcactgtg atttgcaactgtcctaaccttggattacatcaagatctttgttgccatctctgtgctgag tataataaatacagaaattaaaatatactggggctcctatcgccatcctgtaaacgccac cgtcttcacccgcccaagcaaaccaaggcgaaccttacctggtacttttaacatctctcc ctctgtgatttacaacagtttcaacccagacggagtgagtctacgagagaacctctccga gctcagctactccatcagaaaaaacaccaccctccttacctgccgggaacgtacgagtgc gtcaccggccgctgcaccacacctaccgcctgaccgtaaaccagactttttccggacaga cctcaataactctgtttaccagaacaggaggtgagcttagaaaacccttagggtattagg ccaaaggcgcagctactgtggggtttatgaacaattcaagcaactctacgggctattcta attcaggtttctctagaatcggggttggggttattctctgtcttgtgattctctttattc ttatactaacgcttctctgcctaaggctcgccgcctgctgtgtgcacatttgcatttatt gtcagctttttaaacgctggggtcgccacccaagatgattaggtacataatcctaggttt actcacccttgcgtcagcccacggtaccacccaaaaggtggattttaaggagccagcctg taatgttacattcgcagctgaagctaatgagtgcaccactcttataaaatgcaccacaga acatgaaaagctgcttattcgccacaaaaacaaaattggcaagtatgctgtttatgctat ttggcagccaggtgacactacagagtataatgttacagttttccagggtaaaagtcataa aacttttatgtatacttttccattttatgaaatgtgcgacattaccatgtacatgagcaa acagtataagttgtggcccccacaaaattgtgtggaaaacactggcactttctgctgcac tgctatgctaattacagtgctcgctttggtctgtaccctactctatattaaatacaaaag cagacgcagctttattgaggaaaagaaaatgccttaatttactaagttacaaagctaatg tcaccactaactgctttactcgctgcttgcaaaacaaattcaaaaagttagcattataat tagaataggatttaaaccccccggtcatttcctgctcaataccattcccctgaacaattg actctatgtgggatatgctccagcgctacaaccttgaagtcaggcttcctggatgtcage atctgactttggccagcacctgtcccgcggatttgttccagtccaactacagcgacccac cctaacagagatgaccaacacaaccaacgcggccgccgctaccggacttacatctaccac aaatacaccccaagtttctgcctttgtcaataactgggataacttgggcatgtggtggtt ctccatagcgcttatgtttgtatgccttattattatgtggctcatctgctgcctaaagcg caaacgcgcccgaccacccatctatagtcccatcattgtgctacacccaaacaatgatgg aatccatagattggacggactgaaacacatgttcttttctcttacagtatgattaaatga gacatgattcctcgagtttttatattactgacccttgttgcgcttttttgtgcgtgctcc acattggctgcggtttctcacatcgaagtagactgcattccagccttcacagtctatttg ctttacggatttgtcaccctcacgctcatctgcagcctcatcactgtggtcatcgccttt atccagtgcattgactgggtctgtgtgcgctttgcatatctcagacaccatccccagtac agggacaggactatagctgagcttcttagaattctttaattatgaaatttactgtgactt ttctgctgattatttgcaccctatctgcgttttgttccccgacctccaagcctcaaagac atatatcatgcagattcactcgtatatggaatattccaagttgctacaatgaaaaaagcg atctttccgaagcctggttatatgcaatcatctctgttatggtgttctgcagtaccatct tagccctagctatatatccctaccttgacattggctggaaacgaatagatgccatgaacc acccaactttccccgcgcccgctatgcttccactgcaacaagttgttgccggcggctttg tcccagccaatcagcctcgccccacttctcccacccccactgaaatcagctactttaatc taacaggaggagatgactgacaccctagatctagaaatggacggaattattacagagcag cgcctgctagaaagacgcagggcagcggccgagcaacagcgcatgaatcaagagctccaa gacatggttaacttgcaccagtgcaaaaggggtatcttttgtctggtaaagcaggccaaa gtcacctacgacagtaataccaccggacaccgccttagctacaagttgccaaccaagcgt cagaaattggtggtcatggtgggagaaaagcccattaccataactcagcactcggtagaa accgaaggctgcattcactcaccttgtcaaggacctgaggatctctgcacccttattaag accctgtgcggtctcaaagatcttattccctttaactaataaaaaaaaataataaagcat cacttacttaaaatcagttagcaaatttctgtccagtttattcagcagcacctccttgcc ctcctcccagctctggtattgcagcttcctcctggctgcaaactttctccacaatctaaa tggaatgtcagtttcctcctgttcctgtccatccgcacccactatcttcatgttgttgca gatgaagcgcgcaagaccgtctgaagataccttcaaccccgtgtatccatatgacacgga aaccggtcctccaactgtgccttttcttactcctccctttgtatcccccaatgggtttca agagagtccccctggggtactctctttgcgcctatccgaacctctagttacctccaatgg catgcttgcgctcaaaatgggcaacggcctctctctggacgaggccggcaaccttacctc ccaaaatgtaaccactgtgagcccacctctcaaaaaaaccaagtcaaacataaacctgga aatatctgcacccctcacagttacctcagaagccctaactgtggctgccgccgcacctct aatggtcgcgggcaacacactcaccatgcaatcacaggccccgctaaccgtgcacgactc caaacttagcattgccacccaaggacccctcacagtgtcagaaggaaagctagccctgca aacatcaggccccctcaccaccaccgatagcagtacccttactatcactgcctcaccccc tctaactactgccactggtagcttgggcattgacttgaaagagcccatttatacacaaaa tggaaaactaggactaaagtacggggctcctttgcatgtaacagacgacctaaacacttt gaccgtagcaactggtccaggtgtgactattaataatacttccttgcaaactaaagttac tggagccttgggttttgattcacaaggcaatatgcaacttaatgtagcaggaggactaag gattgattctcaaaacagacgccttatacttgatgttagttatccgtttgatgctcaaaa ccaactaaatctaagactaggacagggccctctttttataaactcagcccacaacttgga tattaactacaacaaaggcctttacttgtttacagcttcaaacaattccaaaaagcttga ggttaacctaagcactgccaaggggttgatgtttgacgctacagccatagccattaatgc aggagatgggcttgaatttggttcacctaatgcaccaaacacaaatcccctcaaaacaaa aattggccatggcctagaatttgattcaaacaaggctatggttcctaaactaggaactgg ccttagttttgacagcacaggtgccattacagtaggaaacaaaaataatgataagctaac tttgtggaccacaccagctccatctcctaactgtagactaaatgcagagaaagatgctaa actcactttggtcttaacaaaatgtggcagtcaaatacttgctacagtttcagttttggc tgttaaaggcagtttggctccaatatctggaacagttcaaagtgctcatcttattataag atttgacgaaaatggagtgctactaaacaattccttcctggacccagaatattggaactt tagaaatggagatcttactgaaggcacagcctatacaaacgctgttggatttatgcctaa cctatcagcttatccaaaatctcacggtaaaactgccaaaagtaacattgtcagtcaagt ttacttaaacggagacaaaactaaacctgtaacactaaccattacactaaacggtacaca ggaaacaggagacacaactccaagtgcatactctatgtcattttcatgggactggtctgg ccacaactacattaatgaaatatttgccacatcctcttacactttttcatacattgccca agaataaagaatcgtttgtgttatgtttcaacgtgtttatttttcaattgcagaaaattt caagtcatttttcattcagtagtatagccccaccaccacatagcttatacagatcaccgt accttaatcaaactcacagaaccctagtattcaacctgccacctccctcccaacacacag agtacacagtcctttctccccggctggccttaaaaagcatcatatcatgggtaacagaca tattcttaggtgttatattccacacggtttcctgtcgagccaaacgctcatcagtgatat taataaactccccgggcagctcacttaagttcatgtcgctgtccagctgctgagccacag gctgctgtccaacttgcggttgcttaacgggcggcgaaggagaagtccacgcctacatgg gggtagagtcataatcgtgcatcaggatagggcggtggtgctgcagcagcgcgcgaataa actgctgccgccgccgctccgtcctgcaggaatacaacatggcagtggtctcctcagcga tgattcgcaccgcccgcagcataaggcgccttgtcctccgggcacagcagcgcaccctga tctcacttaaatcagcacagtaactgcagcacagcaccacaatattgttcaaaatcccac agtgcaaggcgctgtatccaaagctcatggcggggaccacagaacccacgtggccatcat accacaagcgcaggtagattaagtggcgacccctcataaacacgctggacataaacatta cctcttttggcatgttgtaattcaccacctcccggtaccatataaacctctgattaaaca tggcgccatccaccaccatcctaaaccagctggccaaaacctgcccgccggctatacact gcagggaaccgggactggaacaatgacagtggagagcccaggactcgtaaccatggatca tcatgctcgtcatgatatcaatgttggcacaacacaggcacacgtgcatacacttcctca ggattacaagctcctcccgcgttagaaccatatcccagggaacaacccattcctgaatca gcgtaaatcccacactgcagggaagacctcgcacgtaactcacgttgtgcattgtcaaag tgttacattcgggcagcagcggatgatcctccagtatggtagcgcgggtttctgtctcaa aaggaggtagacgatccctactgtacggagtgcgccgagacaaccgagatcgtgttggtc gtagtgtcatgccaaatggaacgccggacgtagtcatatttcctgaagcaaaaccaggtg cgggcgtgacaaacagatctgcgtctccggtctcgccgcttagatcgctctgtgtagtag ttgtagtatatccactctctcaaagcatccaggcgccccctggcttcgggttctatgtaa actccttcatgcgccgctgccctgataacatccaccaccgcagaataagccacacccagc caacctacacattcgttctgcgagtcacacacgggaggagcgggaagagctggaagaacc atgtttttttttttattccaaaagattatccaaaacctcaaaatgaagatctattaagtg aacgcgctcccctccggtggcgtggtcaaactctacagccaaagaacagataatggcatt tgtaagatgttgcacaatggcttccaaaaggcaaacggccctcacgtccaagtggacgta aaggctaaacccttcagggtgaatctcctctataaacattccagcaccttcaaccatgcc caaataattctcatctcgccaccttctcaatatatctctaagcaaatcccgaatattaag tccggccattgtaaaaatctgctccagagcgccctccaccttcagcctcaagcagcgaat catgattgcaaaaattcaggttcctcacagacctgtataagattcaaaagcggaacatta acaaaaataccgcgatcccgtaggtcccttcgcagggccagctgaacataatcgtgcagg tctgcacggaccagcgcggccacttccccgccaggaaccttgacaaaagaacccacactg attatgacacgcatactcggagctatgctaaccagcgtagccccgatgtaagctttgttg catgggcggcgatataaaatgcaaggtgctgctcaaaaaatcaggcaaagcctcgcgcaa aaaagaaagcacatcgtagtcatgctcatgcagataaaggcaggtaagctccggaaccac cacagaaaaagacaccatttttctctcaaacatgtctgcgggtttctgcataaacacaaa ataaaataacaaaaaaacatttaaacattagaagcctgtcttacaacaggaaaaacaacc cttataagcataagacggactacggccatgccggcgtgaccgtaaaaaaactggtcaccg tgattaaaaagcaccaccgacagctcctcggtcatgtccggagtcataatgtaagactcg gtaaacacatcaggttgattcatcggtcagtgctaaaaagcgaccgaaatagcccggggg aatacatacccgcaggcgtagagacaacattacagcccccataggaggtataacaaaatt aataggagagaaaaacacataaacacctgaaaaaccctcctgcctaggcaaaatagcacc ctcccgctccagaacaacatacagcgcttcacagcggcagcctaacagtcagccttacca gtaaaaaagaaaacctattaaaaaaacaccactcgacacggcaccagctcaatcagtcac agtgtaaaaaagggccaagtgcagagcgagtatatataggactaaaaaatgacgtaacgg ttaaagtccacaaaaaacacccagaaaaccgcacgcgaacctacgcccagaaacgaaagc caaaaaacccacaacttcctcaaatcgtcacttccgttttcccacgttacgtaacttccc attttaagaaaactacaattcccaacacatacaagttactccgccctaaaacctacgtca cccgccccgttcccacgccccgcgccacgtcacaaactccaccccctcattatcatattg gcttcaatccaaaataaggtatattattgatgatgatttaaatgccgcagtactgttgta attcattaagcattctgccgacatggaagccatcacaaacggcatgatgaacctgaatcg ccagcggcatcagcaccttgtcgccttgcgtataatatttgcccatggtgaaaacggggg cgaagaagttgtccatattggccacgtttaaatcaaaactggtgaaactcacccagggat tggctgagacgaaaaacatattctcaataaaccctttagggaaataggccaggttttcac cgtaacacgccacatcttgcgaatatatgtgtagaaactgccggaaatcgtcgtggtatt cactccagagcgatgaaaacgtttcagtttgctcatggaaaacggtgtaacaagggtgaa cactatcccatatcaccagctcaccgtctttcattgccatacggaattccggatgagcat tcatcaggcgggcaagaatgtgaataaaggccggataaaacttgtgcttatttttcttta cggtctttaaaaaggccgtaatatccagctgaacggtctggttataggtacattgagcaa ctgactgaaatgcctcaaaatgttctttacgatgccattgggatatatcaacggtggtat atccagtgatttttttctccattttagcttccttagctcctgaaaatctcgataactcaa aaaatacgcccggtagtgatcttatttcattatggtgaaagttggaacctcttacgtgcc gatcaacgtctcattttcgccaaaagttggcccagggcttcccggtatcaacagggacac caggatttatttattctgcgaagtgatcttccgtcacaggtatttattcgcgataagctc atggagcggcgtaaccgtcgcacaggaaggacagagaaagcgcggatctgggaagtgacg gacagaacggtcaggacctggattggggaggcggttgccgccgctgctgctgacggtgtg acgttctctgttccggtcacaccacatacgttccgccattcctatgcgatgcacatgctg tatgccggtataccgctgaaagttctgcaaagcctgatgggacataagtccatcagttca acggaagtctacacgaaggtttttgcgctggatgtggctgcccggcaccgggtgcagttt gcgatgccggagtctgatgcggttgcgatgctgaaacaattatcctgagaataaatgcct tggcctttatatggaaatgtggaactgagtggatatgctgtttttgtctgttaaacagag aagctggctgttatccactgagaagcgaacgaaacagtcgggaaaatctcccattatcgt agagatccgcattattaatctcaggagcctgtgtagcgtttataggaagtagtgttctgt catgatgcctgcaagcggtaacgaaaacgatttgaatatgccttcaggaacaatagaaat cttcgtgcggtgttacgttgaagtggagcggattatgtcagcaatggacagaacaaccta atgaacacagaaccatgatgtggtctgtccttttacagccagtagtgctcgccgcagtcg agcgacagggcgaagccctcgagtgagcgaggaagcaccagggaacagcacttatatatt ctgcttacacacgatgcctgaaaaaacttcccttggggttatccacttatccacggggat atttttataattattttttttatagtttttagatcttcttttttagagcgccttgtaggc ctttatccatgctggttctagagaaggtgttgtgacaaattgccctttcagtgtgacaaa tcaccctcaaatgacagtcctgtctgtgacaaattgcccttaaccctgtgacaaattgcc ctcagaagaagctgttttttcacaaagttatccctgcttattgactcttttttatttagt gtgacaatctaaaaacttgtcacacttcacatggatctgtcatggcggaaacagcggtta tcaatcacaagaaacgtaaaaatagcccgcgaatcgtccagtcaaacgacctcactgagg cggcatatagtctctcccgggatcaaaaacgtatgctgtatctgttcgttgaccagatca gaaaatctgatggcaccctacaggaacatgacggtatctgcgagatccatgttgctaaat atgctgaaatattcggattgacctctgcggaagccagtaaggatatacggcaggcattga agagtttcgcggggaaggaagtggttttttatcgccctgaagaggatgccggcgatgaaa aaggctatgaatcttttccttggtttatcaaacgtgcgcacagtccatccagagggcttt acagtgtacatatcaacccatatctcattcccttctttatcgggttacagaaccggttta cgcagtttcggcttagtgaaacaaaagaaatcaccaatccgtatgccatgcgtttatacg aatccctgtgtcagtatcgtaagccggatggctcaggcatcgtctctctgaaaatcgact ggatcatagagcgttaccagctgcctcaaagttaccagcgtatgcctgacttccgccgcc gcttcctgcaggtctgtgttaatgagatcaacagcagaactccaatgcgcctctcataca ttgagaaaaagaaaggccgccagacgactcatatcgtattttccttccgcgatatcactt ccatgacgacaggatagtctgagggttatctgtcacagatttgagggtggttcgtcacat ttgttctgacctactgagggtaatttgtcacagttttgctgtttccttcagcctgcatgg attttctcatactttttgaactgtaatttttaaggaagccaaatttgagggcagtttgtc acagttgatttccttctctttcccttcgtcatgtgacctgatatcgggggttagttcgtc atcattgatgagggttgattatcacagtttattactctgaattggctatccgcgtgtgta cctctacctggagtttttcccacggtggatatttcttcttgcgctgagcgtaagagctat ctgacagaacagttcttctttgcttcctcgccagttcgctcgctatgctcggttacacgg ctgcggcgagcgctagtgataataagtgactgaggtatgtgctcttcttatctccttttg tagtgttgctcttattttaaacaactttgcggttttttgatgactttgcgattttgttgt tgctttgcagtaaattgcaagatttaataaaaaaacgcaaagcaatgattaaaggatgtt cagaatgaaactcatggaaacacttaaccagtgcataaacgctggtcatgaaatgacgaa ggctatcgccattgcacagtttaatgatgacagcccggaagcgaggaaaataacccggcg ctggagaataggtgaagcagcggatttagttggggtttcttctcaggctatcagagatgc cgagaaagcagggcgactaccgcacccggatatggaaattcgaggacgggttgagcaacg tgttggttatacaattgaacaaattaatcatatgcgtgatgtgtttggtacgcgattgcg acgtgctgaagacgtatttccaccggtgatcggggttgctgcccataaaggtggcgttta caaaacctcagtttctgttcatcttgctcaggatctggctctgaaggggctacgtgtttt gctcgtggaaggtaacgacccccagggaacagcctcaatgtatcacggatgggtaccaga tcttcatattcatgcagaagacactctcctgcctttctatcttggggaaaaggacgatgt cacttatgcaataaagcccacttgctggccggggcttgacattattccttcctgtctggc tctgcaccgtattgaaactgagttaatgggcaaatttgatgaaggtaaactgcccaccga tccacacctgatgctccgactggccattgaaactgttgctcatgactatgatgtcatagt tattgacagcgcgcctaacctgggtatcggcacgattaatgtcgtatgtgctgctgatgt gctgattgttcccacgcctgctgagttgtttgactacacctccgcactgcagtttttcga tatgcttcgtgatctgctcaagaacgttgatcttaaagggttcgagcctgatgtacgtat tttgcttaccaaatacagcaatagtaatggctctcagtccccgtggatggaggagcaaat tcgggatgcctggggaagcatggttctaaaaaatgttgtacgtgaaacggatgaagttgg taaaggtcagatccggatgagaactgtttttgaacaggccattgatcaacgctcttcaac tggtgcctggagaaatgctctttctatttgggaacctgtctgcaatgaaattttcgatcg tctgattaaaccacgctgggagattagataatgaagcgtgcgcctgttattccaaaacat acgctcaatactcaaccggttgaagatacttcgttatcgacaccagctgccccgatggtg gattcgttaattgcgcgcgtaggagtaatggctcgcggtaatgccattactttgcctgta tgtggtcgggatgtgaagtttactcttgaagtgctccggggtgatagtgttgagaagacc tctcgggtatggtcaggtaatgaacgtgaccaggagctgcttactgaggacgcactggat gatctcatcccttcttttctactgactggtcaacagacaccggcgttcggtcgaagagta tctggtgtcatagaaattgccgatgggagtcgccgtcgtaaagctgctgcacttaccgaa agtgattatcgtgttctggttggcgagctggatgatgagcagatggctgcattatccaga ttgggtaacgattatcgcccaacaagtgcttatgaacgtggtcagcgttatgcaagccga ttgcagaatgaatttgctggaaatatttctgcgctggctgatgcggaaaatatttcacgt aagattattacccgctgtatcaacaccgccaaattgcctaaatcagttgttgctcttttt tctcaccccggtgaactatctgcccggtcaggtgatgcacttcaaaaagcctttacagat aaagaggaattacttaagcagcaggcatctaaccttcatgagcagaaaaaagctggggtg atatttgaagctgaagaagttatcactcttttaacttctgtgcttaaaacgtcatctgca tcaagaactagtttaagctcacgacatcagtttgctcctggagcgacagtattgtataag ggcgataaaatggtgcttaacctggacaggtctcgtgttccaactgagtgtatagagaaa attgaggccattcttaaggaacttgaaaagccagcaccctgatgcgaccacgttttagtc tacgtttatctgtctttacttaatgtcctttgttacaggccagaaagcataactggcctg aatattctctctgggcccactgttccacttgtatcgtcggtctgataatcagactgggac cacggtcccactcgtatcgtcggtctgattattagtctgggaccacggtcccactcgtat cgtcggtctgattattagtctgggaccacggtcccactcgtatcgtcggtctgataatca gactgggaccacggtcccactcgtatcgtcggtctgattattagtctgggaccatggtcc cactcgtatcgtcggtctgattattagtctgggaccacggtcccactcgtatcgtcggtc tgattattagtctggaaccacggtcccactcgtatcgtcggtctgattattagtctggga ccacggtcccactcgtatcgtcggtctgattattagtctgggaccacgatcccactcgtg ttgtcggtctgattatcggtctgggaccacggtcccacttgtattgtcgatcagactatc agcgtgagactacgattccatcaatgcctgtcaagggcaagtattgacatgtcgtcgtaa cctgtagaacggagtaacctcggtgtgcggttgtatgcctgctgtggattgctgctgtgt cctgcttatccacaacattttgcgcacggttatgtggacaaaatacctgttaccatttcc atttaaatcatcatcaataatataccttattttggattgaagccaatatgataatgaggg ggtggagtttgtgacgtggcgcggggcgtgggaacggggcgggtgacgtagtagtgtggc ggaagtgtgatgttgcaagtgtggcggaacacatgtaagcgacggatgtggcaaaagtga cgtttttggtgtgcgccggtgtacacaggaagtgacaattttcgcgcggttttaggcgga tgttgtagtaaatttgggcgtaaccgagtaagatttggccattttcgcgggaaaactgaa taagaggaagtgaaatctgaataattttgtgttactcatagcgcgtaatatttgtctagg gccgcggggactttgaccgtttacgtggagactcgcccaggtgtttttctcaggtgtttt ccgcgttccgggtcaaagttggcgtttt

SEQ ID NO: 5 (pGS66)

TTCGAAATTTAAATCATCATCAATAATATACCTTATTTTGGATTGAAGCCAATATGATAA TGAGGGGGTGGAG TTTGTGACGTGGCGCGGGGCGTGGGAACGGGGCGGGTGACGTAGTAGTGTGGCGGAAGTG TGATGTTGCAAGT GTGGCGGAACACATGTAAGCGACGGATGTGGCAAAAGTGACGTTTTTGGTGTGCGCCGGT GTACACAGGAAGT GACAATTTTCGCGCGGTTTTAGGCGGATGTTGTAGTAAATTTGGGCGTAACCGAGTAAGA TTTGGCCATTTTC GCGGGAAAACTGAATAAGAGGAAGTGAAATCTGAATAATTTTGTGTTACTCATAGCGCGT AATATTTGTCTAG GGCCGCGGGGACTTTGACCGTTTACGTGGAGACTCGCCCAGGTGTTTTTCTCAGGTGTTT TCCGCGTTCCGGG TCAAAGTTGGCGTTTTGATGGCGTCCCTTAATTAAGGATCCAGATCTGTGGGCGTGGCTT AAGGGTGGGAAAG AATATATAAGGTGGGGGTCTTATGTAGTTTTGTATCTGTTTTGCAGCAGCCGCCGCCGCC ATGAGCACCAACT CGTTTGATGGAAGCATTGTGAGCTCATATTTGACAACGCGCATGCCCCCATGGGCCGGGG TGCGTCAGAATGT GATGGGCTCCAGCATTGATGGTCGCCCCGTCCTGCCCGCAAACTCTACTACCTTGACCTA CGAGACCGTGTCT GGAACGCCGTTGGAGACTGCAGCCTCCGCCGCCGCTTCAGCCGCTGCAGCCACCGCCCGC GGGATTGTGACTG ACTTTGCTTTCCTGAGCCCGCTTGCAAGCAGTGCAGCTTCCCGTTCATCCGCCCGCGATG ACAAGTTGACGGC TCTTTTGGCACAATTGGATTCTTTGACCCGGGAACTTAATGTCGTTTCTCAGCAGCTGTT GGATCTGCGCCAG CAGGTTTCTGCCCTGAAGGCTTCCTCCCCTCCCAATGCGGTTTAAAACATAAATAAAAAA CCAGACTCTGTTT GGATTTGGATCAAGCAAGTGTCTTGCTGTCTTTATTTAGGGGTTTTGCGCGCGCGGTAGG CCCGGGACCAGCG GTCTCGGTCGTTGAGGGTCCTGTGTATTTTTTCCAGGACGTGGTAAAGGTGACTCTGGAT GTTCAGATACATG GGCATAAGCCCGTCTCTGGGGTGGAGGTAGCACCACTGCAGAGCTTCATGCTGCGGGGTG GTGTTGTAGATGA TCCAGTCGTAGCAGGAGCGCTGGGCGTGGTGCCTAAAAATGTCTTTCAGTAGCAAGCTGA TTGCCAGGGGCAG GCCCTTGGTGTAAGTGTTTACAAAGCGGTTAAGCTGGGATGGGTGCATACGTGGGGATAT GAGATGCATCTTG GACTGTATTTTTAGGTTGGCTATGTTCCCAGCCATATCCCTCCGGGGATTCATGTTGTGC AGAACCACCAGCA CAGTGTATCCGGTGCACTTGGGAAATTTGTCATGTAGCTTAGAAGGAAATGCGTGGAAGA ACTTGGAGACGCC CTTGTGACCTCCAAGATTTTCCATGCATTCGTCCATAATGATGGCAATGGGCCCACGGGC GGCGGCCTGGGCG AAGATATTTCTGGGATCACTAACGTCATAGTTGTGTTCCAGGATGAGATCGTCATAGGCC ATTTTTACAAAGC GCGGGCGGAGGGTGCCAGACTGCGGTATAATGGTTCCATCCGGCCCAGGGGCGTAGTTAC CCTCACAGATTTG CATTTCCCACGCTTTGAGTTCAGATGGGGGGATCATGTCTACCTGCGGGGCGATGAAGAA AACGGTTTCCGGG GTAGGGGAGATCAGCTGGGAAGAAAGCAGGTTCCTGAGCAGCTGCGACTTACCGCAGCCG GTGGGCCCGTAAA TCACACCTATTACCGGGTGCAACTGGTAGTTAAGAGAGCTGCAGCTGCCGTCATCCCTGA GCAGGGGGGCCAC TTCGTTAAGCATGTCCCTGACTCGCATGTTTTCCCTGACCAAATCCGCCAGAAGGCGCTC GCCGCCCAGCGAT AGCAGTTCTTGCAAGGAAGCAAAGTTTTTCAACGGTTTGAGACCGTCCGCCGTAGGCATG CTTTTGAGCGTTT GACCAAGCAGTTCCAGGCGGTCCCACAGCTCGGTCACCTGCTCTACGGCATCTCGATCCA GCATATCTCCTCG TTTCGCGGGTTGGGGCGGCTTTCGCTGTACGGCAGTAGTCGGTGCTCGTCCAGACGGGCC AGGGTCATGTCTT TCCACGGGCGCAGGGTCCTCGTCAGCGTAGTCTGGGTCACGGTGAAGGGGTGCGCTCCGG GCTGCGCGCTGGC CAGGGTGCGCTTGAGGCTGGTCCTGCTGGTGCTGAAGCGCTGCCGGTCTTCGCCCTGCGC GTCGGCCAGGTAG CATTTGACCATGGTGTCATAGTCCAGCCCCTCCGCGGCGTGGCCCTTGGCGCGCAGCTTG CCCTTGGAGGAGG CGCCGCACGAGGGGCAGTGCAGACTTTTGAGGGCGTAGAGCTTGGGCGCGAGAAATACCG ATTCCGGGGAGTA GGCATCCGCGCCGCAGGCCCCGCAGACGGTCTCGCATTCCACGAGCCAGGTGAGCTCTGG CCGTTCGGGGTCA AAAACCAGGTTTCCCCCATGCTTTTTGATGCGTTTCTTACCTCTGGTTTCCATGAGCCGG TGTCCACGCTCGG TGACGAAAAGGCTGTCCGTGTCCCCGTATACAGACTTGAGAGGCCTGTCCTCGAGCGGTG TTCCGCGGTCCTC CTCGTATAGAAACTCGGACCACTCTGAGACAAAGGCTCGCGTCCAGGCCAGCACGAAGGA GGCTAAGTGGGAG GGGTAGCGGTCGTTGTCCACTAGGGGGTCCACTCGCTCCAGGGTGTGAAGACACATGTCG CCCTCTTCGGCAT CAAGGAAGGTGATTGGTTTGTAGGTGTAGGCCACGTGACCGGGTGTTCCTGAAGGGGGGC TATAAAAGGGGGT GGGGGCGCGTTCGTCCTCACTCTCTTCCGCATCGCTGTCTGCGAGGGCCAGCTGTTGGGG TGAGTACTCCCTC TGAAAAGCGGGCATGACTTCTGCGCTAAGATTGTCAGTTTCCAAAAACGAGGAGGATTTG ATATTCACCTGGC CCGCGGTGATGCCTTTGAGGGTGGCCGCATCCATCTGGTCAGAAAAGACAATCTTTTTGT TGTCAAGCTTGGT GGCAAACGACCCGTAGAGGGCGTTGGACAGCAACTTGGCGATGGAGCGCAGGGTTTGGTT TTTGTCGCGATCG GCGCGCTCCTTGGCCGCGATGTTTAGCTGCACGTATTCGCGCGCAACGCACCGCCATTCG GGAAAGACGGTGG TGCGCTCGTCGGGCACCAGGTGCACGCGCCAACCGCGGTTGTGCAGGGTGACAAGGTCAA CGCTGGTGGCTAC CTCTCCGCGTAGGCGCTCGTTGGTCCAGCAGAGGCGGCCGCCCTTGCGCGAGCAGAATGG CGGTAGGGGGTCT AGCTGCGTCTCGTCCGGGGGGTCTGCGTCCACGGTAAAGACCCCGGGCAGCAGGCGCGCG TCGAAGTAGTCTA TCTTGCATCCTTGCAAGTCTAGCGCCTGCTGCCATGCGCGGGCGGCAAGCGCGCGCTCGT ATGGGTTGAGTGG GGGACCCCATGGCATGGGGTGGGTGAGCGCGGAGGCGTACATGCCGCAAATGTCGTAAAC GTAGAGGGGCTCT CTGAGTATTCCAAGATATGTAGGGTAGCATCTTCCACCGCGGATGCTGGCGCGCACGTAA TCGTATAGTTCGT GCGAGGGAGCGAGGAGGTCGGGACCGAGGTTGCTACGGGCGGGCTGCTCTGCTCGGAAGA CTATCTGCCTGAA GATGGCATGTGAGTTGGATGATATGGTTGGACGCTGGAAGACGTTGAAGCTGGCGTCTGT GAGACCTACCGCG TCACGCACGAAGGAGGCGTAGGAGTCGCGCAGCTTGTTGACCAGCTCGGCGGTGACCTGC ACGTCTAGGGCGC AGTAGTCCAGGGTTTCCTTGATGATGTCATACTTATCCTGTCCCTTTTTTTTCCACAGCT CGCGGTTGAGGAC AAACTCTTCGCGGTCTTTCCAGTACTCTTGGATCGGAAACCCGTCGGCCTCCGAACGGTA AGAGCCTAGCATG TAGAACTGGTTGACGGCCTGGTAGGCGCAGCATCCCTTTTCTACGGGTAGCGCGTATGCC TGCGCGGCCTTCC GGAGCGAGGTGTGGGTGAGCGCAAAGGTGTCCCTGACCATGACTTTGAGGTACTGGTATT TGAAGTCAGTGTC GTCGCATCCGCCCTGCTCCCAGAGCAAAAAGTCCGTGCGCTTTTTGGAACGCGGATTTGG CAGGGCGAAGGTG ACATCGTTGAAGAGTATCTTTCCCGCGCGAGGCATAAAGTTGCGTGTGATGCGGAAGGGT CCCGGCACCTCGG AACGGTTGTTAATTACCTGGGCGGCGAGCACGATCTCGTCAAAGCCGTTGATGTTGTGGC CCACAATGTAAAG TTCCAAGAAGCGCGGGATGCCCTTGATGGAAGGCAATTTTTTAAGTTCCTCGTAGGTGAG CTCTTCAGGGGAG CTGAGCCCGTGCTCTGAAAGGGCCCAGTCTGCAAGATGAGGGTTGGAAGCGACGAATGAG CTCCACAGGTCAC GGGCCATTAGCATTTGCAGGTGGTCGCGAAAGGTCCTAAACTGGCGACCTATGGCCATTT TTTCTGGGGTGAT GCAGTAGAAGGTAAGCGGGTCTTGTTCCCAGCGGTCCCATCCAAGGTTCGCGGCTAGGTC TCGCGCGGCAGTC ACTAGAGGCTCATCTCCGCCGAACTTCATGACCAGCATGAAGGGCACGAGCTGCTTCCCA AAGGCCCCCATCC AAGTATAGGTCTCTACATCGTAGGTGACAAAGAGACGCTCGGTGCGAGGATGCGAGCCGA TCGGGAAGAACTG GATCTCCCGCCACCAATTGGAGGAGTGGCTATTGATGTGGTGAAAGTAGAAGTCCCTGCG ACGGGCCGAACAC TCGTGCTGGCTTTTGTAAAAACGTGCGCAGTACTGGCAGCGGTGCACGGGCTGTACATCC TGCACGAGGTTGA CCTGACGACCGCGCACAAGGAAGCAGAGTGGGAATTTGAGCCCCTCGCCTGGCGGGTTTG GCTGGTGGTCTTC TACTTCGGCTGCTTGTCCTTGACCGTCTGGCTGCTCGAGGGGAGTTACGGTGGATCGGAC CACCACGCCGCGC GAGCCCAAAGTCCAGATGTCCGCGCGCGGCGGTCGGAGCTTGATGACAACATCGCGCAGA TGGGAGCTGTCCA TGGTCTGGAGCTCCCGCGGCGTCAGGTCAGGCGGGAGCTCCTGCAGGTTTACCTCGCATA GACGGGTCAGGGC GCGGGCTAGATCCAGGTGATACCTAATTTCCAGGGGCTGGTTGGTGGCGGCGTCGATGGC TTGCAAGAGGCCG CATCCCCGCGGCGCGACTACGGTACCGCGCGGCGGGCGGTGGGCCGCGGGGGTGTCCTTG GATGATGCATCTA AAAGCGGTGACGCGGGCGAGCCCCCGGAGGTAGGGGGGGCTCCGGACCCGCCGGGAGAGG GGGCAGGGGCACG TCGGCGCCGCGCGCGGGCAGGAGCTGGTGCTGCGCGCGTAGGTTGCTGGCGAACGCGACG ACGCGGCGGTTGA TCTCCTGAATCTGGCGCCTCTGCGTGAAGACGACGGGCCCGGTGAGCTTGAGCCTGAAAG AGAGTTCGACAGA ATCAATTTCGGTGTCGTTGACGGCGGCCTGGCGCAAAATCTCCTGCACGTCTCCTGAGTT GTCTTGATAGGCG ATCTCGGCCATGAACTGCTCGATCTCTTCCTCCTGGAGATCTCCGCGTCCGGCTCGCTCC ACGGTGGCGGCGA GGTCGTTGGAAATGCGGGCCATGAGCTGCGAGAAGGCGTTGAGGCCTCCCTCGTTCCAGA CGCGGCTGTAGAC CACGCCCCCTTCGGCATCGCGGGCGCGCATGACCACCTGCGCGAGATTGAGCTCCACGTG CCGGGCGAAGACG GCGTAGTTTCGCAGGCGCTGAAAGAGGTAGTTGAGGGTGGTGGCGGTGTGTTCTGCCACG AAGAAGTACATAA CCCAGCGTCGCAACGTGGATTCGTTGATATCCCCCAAGGCCTCAAGGCGCTCCATGGCCT CGTAGAAGTCCAC GGCGAAGTTGAAAAACTGGGAGTTGCGCGCCGACACGGTTAACTCCTCCTCCAGAAGACG GATGAGCTCGGCG ACAGTGTCGCGCACCTCGCGCTCAAAGGCTACAGGGGCCTCTTCTTCTTCTTCAATCTCC TCTTCCATAAGGG CCTCCCCTTCTTCTTCTTCTGGCGGCGGTGGGGGAGGGGGGACACGGCGGCGACGACGGC GCACCGGGAGGCG GTCGACAAAGCGCTCGATCATCTCCCCGCGGCGACGGCGCATGGTCTCGGTGACGGCGCG GCCGTTCTCGCGG GGGCGCAGTTGGAAGACGCCGCCCGTCATGTCCCGGTTATGGGTTGGCGGGGGGCTGCCA TGCGGCAGGGATA CGGCGCTAACGATGCATCTCAACAATTGTTGTGTAGGTACTCCGCCGCCGAGGGACCTGA GCGAGTCCGCATC GACCGGATCGGAAAACCTCTCGAGAAAGGCGTCTAACCAGTCACAGTCGCAAGGTAGGCT GAGCACCGTGGCG GGCGGCAGCGGGCGGCGGTCGGGGTTGTTTCTGGCGGAGGTGCTGCTGATGATGTAATTA AAGTAGGCGGTCT TGAGACGGCGGATGGTCGACAGAAGCACCATGTCCTTGGGTCCGGCCTGCTGAATGCGCA GGCGGTCGGCCAT GCCCCAGGCTTCGTTTTGACATCGGCGCAGGTCTTTGTAGTAGTCTTGCATGAGCCTTTC TACCGGCACTTCT TCTTCTCCTTCCTCTTGTCCTGCATCTCTTGCATCTATCGCTGCGGCGGCGGCGGAGTTT GGCCGTAGGTGGC GCCCTCTTCCTCCCATGCGTGTGACCCCGAAGCCCCTCATCGGCTGAAGCAGGGCTAGGT CGGCGACAACGCG CTCGGCTAATATGGCCTGCTGCACCTGCGTGAGGGTAGACTGGAAGTCATCCATGTCCAC AAAGCGGTGGTAT GCGCCCGTGTTGATGGTGTAAGTGCAGTTGGCCATAACGGACCAGTTAACGGTCTGGTGA CCCGGCTGCGAGA GCTCGGTGTACCTGAGACGCGAGTAAGCCCTCGAGTCAAATACGTAGTCGTTGCAAGTCC GCACCAGGTACTG GTATCCCACCAAAAAGTGCGGCGGCGGCTGGCGGTAGAGGGGCCAGCGTAGGGTGGCCGG GGCTCCGGGGGCG AGATCTTCCAACATAAGGCGATGATATCCGTAGATGTACCTGGACATCCAGGTGATGCCG GCGGCGGTGGTGG AGGCGCGCGGAAAGTCGCGGACGCGGTTCCAGATGTTGCGCAGCGGCAAAAAGTGCTCCA TGGTCGGGACGCT CTGGCCGGTCAGGCGCGCGCAATCGTTGACGCTCTAGACCGTGCAAAAGGAGAGCCTGTA AGCGGGCACTCTT CCGTGGTCTGGTGGATAAATTCGCAAGGGTATCATGGCGGACGACCGGGGTTCGAGCCCC GTATCCGGCCGTC CGCCGTGATCCATGCGGTTACCGCCCGCGTGTCGAACCCAGGTGTGCGACGTCAGACAAC GGGGGAGTGCTCC TTTTGGCTTCCTTCCAGGCGCGGCGGCTGCTGCGCTAGCTTTTTTGGCCACTGGCCGCGC GCAGCGTAAGCGG TTAGGCTGGAAAGCGAAAGCATTAAGTGGCTCGCTCCCTGTAGCCGGAGGGTTATTTTCC AAGGGTTGAGTCG CGGGACCCCCGGTTCGAGTCTCGGACCGGCCGGACTGCGGCGAACGGGGGTTTGCCTCCC CGTCATGCAAGAC CCCGCTTGCAAATTCCTCCGGAAACAGGGACGAGCCCCTTTTTTGCTTTTCCCAGATGCA TCCGGTGCTGCGG CAGATGCGCCCCCCTCCTCAGCAGCGGCAAGAGCAAGAGCAGCGGCAGACATGCAGGGCA CCCTCCCCTCCTC CTACCGCGTCAGGAGGGGCGACATCCGCGGTTGACGCGGCAGCAGATGGTGATTACGAAC CCCCGCGGCGCCG GGCCCGGCACTACCTGGACTTGGAGGAGGGCGAGGGCCTGGCGCGGCTAGGAGCGCCCTC TCCTGAGCGGCAC CCAAGGGTGCAGCTGAAGCGTGATACGCGTGAGGCGTACGTGCCGCGGCAGAACCTGTTT CGCGACCGCGAGG GAGAGGAGCCCGAGGAGATGCGGGATCGAAAGTTCCACGCAGGGCGCGAGCTGCGGCATG GCCTGAATCGCGA GCGGTTGCTGCGCGAGGAGGACTTTGAGCCCGACGCGCGAACCGGGATTAGTCCCGCGCG CGCACACGTGGCG GCCGCCGACCTGGTAACCGCATACGAGCAGACGGTGAACCAGGAGATTAACTTTCAAAAA AGCTTTAACAACC ACGTGCGTACGCTTGTGGCGCGCGAGGAGGTGGCTATAGGACTGATGCATCTGTGGGACT TTGTAAGCGCGCT GGAGCAAAACCCAAATAGCAAGCCGCTCATGGCGCAGCTGTTCCTTATAGTGCAGCACAG CAGGGACAACGAG GCATTCAGGGATGCGCTGCTAAACATAGTAGAGCCCGAGGGCCGCTGGCTGCTCGATTTG ATAAACATCCTGC AGAGCATAGTGGTGCAGGAGCGCAGCTTGAGCCTGGCTGACAAGGTGGCCGCCATCAACT ATTCCATGCTTAG CCTGGGCAAGTTTTACGCCCGCAAGATATACCATACCCCTTACGTTCCCATAGACAAGGA GGTAAAGATCGAG GGGTTCTACATGCGCATGGCGCTGAAGGTGCTTACCTTGAGCGACGACCTGGGCGTTTAT CGCAACGAGCGCA TCCACAAGGCCGTGAGCGTGAGCCGGCGGCGCGAGCTCAGCGACCGCGAGCTGATGCACA GCCTGCAAAGGGC CCTGGCTGGCACGGGCAGCGGCGATAGAGAGGCCGAGTCCTACTTTGACGCGGGCGCTGA CCTGCGCTGGGCC CCAAGCCGACGCGCCCTGGAGGCAGCTGGGGCCGGACCTGGGCTGGCGGTGGCACCCGCG CGCGCTGGCAACG TCGGCGGCGTGGAGGAATATGACGAGGACGATGAGTACGAGCCAGAGGACGGCGAGTACT AAGCGGTGATGTT TCTGATCAGATGATGCAAGACGCAACGGACCCGGCGGTGCGGGCGGCGCTGCAGAGCCAG CCGTCCGGCCTTA ACTCCACGGACGACTGGCGCCAGGTCATGGACCGCATCATGTCGCTGACTGCGCGCAATC CTGACGCGTTCCG GCAGCAGCCGCAGGCCAACCGGCTCTCCGCAATTCTGGAAGCGGTGGTCCCGGCGCGCGC AAACCCCACGCAC GAGAAGGTGCTGGCGATCGTAAACGCGCTGGCCGAAAACAGGGCCATCCGGCCCGACGAG GCCGGCCTGGTCT ACGACGCGCTGCTTCAGCGCGTGGCTCGTTACAACAGCGGCAACGTGCAGACCAACCTGG ACCGGCTGGTGGG GGATGTGCGCGAGGCCGTGGCGCAGCGTGAGCGCGCGCAGCAGCAGGGCAACCTGGGCTC CATGGTTGCACTA AACGCCTTCCTGAGTACACAGCCCGCCAACGTGCCGCGGGGACAGGAGGACTACACCAAC TTTGTGAGCGCAC TGCGGCTAATGGTGACTGAGACACCGCAAAGTGAGGTGTACCAGTCTGGGCCAGACTATT TTTTCCAGACCAG TAGACAAGGCCTGCAGACCGTAAACCTGAGCCAGGCTTTCAAAAACTTGCAGGGGCTGTG GGGGGTGCGGGCT CCCACAGGCGACCGCGCGACCGTGTCTAGCTTGCTGACGCCCAACTCGCGCCTGTTGCTG CTGCTAATAGCGC CCTTCACGGACAGTGGCAGCGTGTCCCGGGACACATACCTAGGTCACTTGCTGACACTGT ACCGCGAGGCCAT AGGTCAGGCGCATGTGGACGAGCATACTTTCCAGGAGATTACAAGTGTCAGCCGCGCGCT GGGGCAGGAGGAC ACGGGCAGCCTGGAGGCAACCCTAAACTACCTGCTGACCAACCGGCGGCAGAAGATCCCC TCGTTGCACAGTT TAAACAGCGAGGAGGAGCGCATTTTGCGCTACGTGCAGCAGAGCGTGAGCCTTAACCTGA TGCGCGACGGGGT AACGCCCAGCGTGGCGCTGGACATGACCGCGCGCAACATGGAACCGGGCATGTATGCCTC AAACCGGCCGTTT ATCAACCGCCTAATGGACTACTTGCATCGCGCGGCCGCCGTGAACCCCGAGTATTTCACC AATGCCATCTTGA ACCCGCACTGGCTACCGCCCCCTGGTTTCTACACCGGGGGATTCGAGGTGCCCGAGGGTA ACGATGGATTCCT CTGGGACGACATAGACGACAGCGTGTTTTCCCCGCAACCGCAGACCCTGCTAGAGTTGCA ACAGCGCGAGCAG GCAGAGGCGGCGCTGCGAAAGGAAAGCTTCCGCAGGCCAAGCAGCTTGTCCGATCTAGGC GCTGCGGCCCCGC GGTCAGATGCTAGTAGCCCATTTCCAAGCTTGATAGGGTCTCTTACCAGCACTCGCACCA CCCGCCCGCGCCT GCTGGGCGAGGAGGAGTACCTAAACAACTCGCTGCTGCAGCCGCAGCGCGAAAAAAACCT GCCTCCGGCATTT CCCAACAACGGGATAGAGAGCCTAGTGGACAAGATGAGTAGATGGAAGACGTACGCGCAG GAGCACAGGGACG TGCCAGGCCCGCGCCCGCCCACCCGTCGTCAAAGGCACGACCGTCAGCGGGGTCTGGTGT GGGAGGACGATGA CTCGGCAGACGACAGCAGCGTCCTGGATTTGGGAGGGAGTGGCAACCCGTTTGCGCACCT TCGCCCCAGGCTG GGGAGAATGTTTTAAAAAAAAAAAAGCATGATGCAAAATAAAAAACTCACCAAGGCCATG GCACCGAGCGTTG GTTTTCTTGTATTCCCCTTAGTATGCGGCGCGCGGCGATGTATGAGGAAGGTCCTCCTCC CTCCTACGAGAGT GTGGTGAGCGCGGCGCCAGTGGCGGCGGCGCTGGGTTCTCCCTTCGATGCTCCCCTGGAC CCGCCGTTTGTGC CTCCGCGGTACCTGCGGCCTACCGGGGGGAGAAACAGCATCCGTTACTCTGAGTTGGCAC CCCTATTCGACAC CACCCGTGTGTACCTGGTGGACAACAAGTCAACGGATGTGGCATCCCTGAACTACCAGAA CGACCACAGCAAC TTTCTGACCACGGTCATTCAAAACAATGACTACAGCCCGGGGGAGGCAAGCACACAGACC ATCAATCTTGACG ACCGGTCGCACTGGGGCGGCGACCTGAAAACCATCCTGCATACCAACATGCCAAATGTGA ACGAGTTCATGTT TACCAATAAGTTTAAGGCGCGGGTGATGGTGTCGCGCTTGCCTACTAAGGACAATCAGGT GGAGCTGAAATAC GAGTGGGTGGAGTTCACGCTGCCCGAGGGCAACTACTCCGAGACCATGACCATAGACCTT ATGAACAACGCGA TCGTGGAGCACTACTTGAAAGTGGGCAGACAGAACGGGGTTCTGGAAAGCGACATCGGGG TAAAGTTTGACAC CCGCAACTTCAGACTGGGGTTTGACCCCGTCACTGGTCTTGTCATGCCTGGGGTATATAC AAACGAAGCCTTC CATCCAGACATCATTTTGCTGCCAGGATGCGGGGTGGACTTCACCCACAGCCGCCTGAGC AACTTGTTGGGCA TCCGCAAGCGGCAACCCTTCCAGGAGGGCTTTAGGATCACCTACGATGATCTGGAGGGTG GTAACATTCCCGC ACTGTTGGATGTGGACGCCTACCAGGCGAGCTTGAAAGATGACACCGAACAGGGCGGGGG TGGCGCAGGCGGC AGCAACAGCAGTGGCAGCGGCGCGGAAGAGAACTCCAACGCGGCAGCCGCGGCAATGCAG CCGGTGGAGGACA TGAACGATCATGCCATTCGCGGCGACACCTTTGCCACACGGGCTGAGGAGAAGCGCGCTG AGGCCGAAGCAGC GGCCGAAGCTGCCGCCCCCGCTGCGCAACCCGAGGTCGAGAAGCCTCAGAAGAAACCGGT GATCAAACCCCTG ACAGAGGACAGCAAGAAACGCAGTTACAACCTAATAAGCAATGACAGCACCTTCACCCAG TACCGCAGCTGGT ACCTTGCATACAACTACGGCGACCCTCAGACCGGAATCCGCTCATGGACCCTGCTTTGCA CTCCTGACGTAAC CTGCGGCTCGGAGCAGGTCTACTGGTCGTTGCCAGACATGATGCAAGACCCCGTGACCTT CCGCTCCACGCGC CAGATCAGCAACTTTCCGGTGGTGGGCGCCGAGCTGTTGCCCGTGCACTCCAAGAGCTTC TACAACGACCAGG CCGTCTACTCCCAACTCATCCGCCAGTTTACCTCTCTGACCCACGTGTTCAATCGCTTTC CCGAGAACCAGAT TTTGGCGCGCCCGCCAGCCCCCACCATCACCACCGTCAGTGAAAACGTTCCTGCTCTCAC AGATCACGGGACG CTACCGCTGCGCAACAGCATCGGAGGAGTCCAGCGAGTGACCATTACTGACGCCAGACGC CGCACCTGCCCCT ACGTTTACAAGGCCCTGGGCATAGTCTCGCCGCGCGTCCTATCGAGCCGCACTTTTTGAG CAAGCATGTCCAT CCTTATATCGCCCAGCAATAACACAGGCTGGGGCCTGCGCTTCCCAAGCAAGATGTTTGG CGGGGCCAAGAAG CGCTCCGACCAACACCCAGTGCGCGTGCGCGGGCACTACCGCGCGCCCTGGGGCGCGCAC AAACGCGGCCGCA CTGGGCGCACCACCGTCGATGACGCCATCGACGCGGTGGTGGAGGAGGCGCGCAACTACA CGCCCACGCCGCC ACCAGTGTCCACAGTGGACGCGGCCATTCAGACCGTGGTGCGCGGAGCCCGGCGCTATGC TAAAATGAAGAGA CGGCGGAGGCGCGTAGCACGTCGCCACCGCCGCCGACCCGGCACTGCCGCCCAACGCGCG GCGGCGGCCCTGC TTAACCGCGCACGTCGCACCGGCCGACGGGCGGCCATGCGGGCCGCTCGAAGGCTGGCCG CGGGTATTGTCAC TGTGCCCCCCAGGTCCAGGCGACGAGCGGCCGCCGCAGCAGCCGCGGCCATTAGTGCTAT GACTCAGGGTCGC AGGGGCAACGTGTATTGGGTGCGCGACTCGGTTAGCGGCCTGCGCGTGCCCGTGCGCACC CGCCCCCCGCGCA ACTAGATTGCAAGAAAAAACTACTTAGACTCGTACTGTTGTATGTATCCAGCGGCGGCGG CGCGCAACGAAGC TATGTCCAAGCGCAAAATCAAAGAAGAGATGCTCCAGGTCATCGCGCCGGAGATCTATGG CCCCCCGAAGAAG GAAGAGCAGGATTACAAGCCCCGAAAGCTAAAGCGGGTCAAAAAGAAAAAGAAAGATGAT GATGATGAACTTG ACGACGAGGTGGAACTGCTGCACGCTACCGCGCCCAGGCGACGGGTACAGTGGAAAGGTC GACGCGTAAAACG TGTTTTGCGACCCGGCACCACCGTAGTCTTTACGCCCGGTGAGCGCTCCACCCGCACCTA CAAGCGCGTGTAT GATGAGGTGTACGGCGACGAGGACCTGCTTGAGCAGGCCAACGAGCGCCTCGGGGAGTTT GCCTACGGAAAGC GGCATAAGGACATGCTGGCGTTGCCGCTGGACGAGGGCAACCCAACACCTAGCCTAAAGC CCGTAACACTGCA GCAGGTGCTGCCCGCGCTTGCACCGTCCGAAGAAAAGCGCGGCCTAAAGCGCGAGTCTGG TGACTTGGCACCC ACCGTGCAGCTGATGGTACCCAAGCGCCAGCGACTGGAAGATGTCTTGGAAAAAATGACC GTGGAACCTGGGC TGGAGCCCGAGGTCCGCGTGCGGCCAATCAAGCAGGTGGCGCCGGGACTGGGCGTGCAGA CCGTGGACGTTCA GATACCCACTACCAGTAGCACCAGTATTGCCACCGCCACAGAGGGCATGGAGACACAAAC GTCCCCGGTTGCC TCAGCGGTGGCGGATGCCGCGGTGCAGGCGGTCGCTGCGGCCGCGTCCAAGACCTCTACG GAGGTGCAAACGG ACCCGTGGATGTTTCGCGTTTCAGCCCCCCGGCGCCCGCGCGGTTCGAGGAAGTACGGCG CCGCCAGCGCGCT ACTGCCCGAATATGCCCTACATCCTTCCATTGCGCCTACCCCCGGCTATCGTGGCTACAC CTACCGCCCCAGA AGACGAGCAACTACCCGACGCCGAACCACCACTGGAACCCGCCGCCGCCGTCGCCGTCGC CAGCCCGTGCTGG CCCCGATTTCCGTGCGCAGGGTGGCTCGCGAAGGAGGCAGGACCCTGGTGCTGCCAACAG CGCGCTACCACCC CAGCATCGTTTAAAAGCCGGTCTTTGTGGTTCTTGCAGATATGGCCCTCACCTGCCGCCT CCGTTTCCCGGTG CCGGGATTCCGAGGAAGAATGCACCGTAGGAGGGGCATGGCCGGCCACGGCCTGACGGGC GGCATGCGTCGTG CGCACCACCGGCGGCGGCGCGCGTCGCACCGTCGCATGCGCGGCGGTATCCTGCCCCTCC TTATTCCACTGAT CGCCGCGGCGATTGGCGCCGTGCCCGGAATTGCATCCGTGGCCTTGCAGGCGCAGAGACA CTGATTAAAAACA AGTTGCATGTGGAAAAATCAAAATAAAAAGTCTGGACTCTCACGCTCGCTTGGTCCTGTA ACTATTTTGTAGA ATGGAAGACATCAACTTTGCGTCTCTGGCCCCGCGACACGGCTCGCGCCCGTTCATGGGA AACTGGCAAGATA TCGGCACCAGCAATATGAGCGGTGGCGCCTTCAGCTGGGGCTCGCTGTGGAGCGGCATTA AAAATTTCGGTTC CACCGTTAAGAACTATGGCAGCAAGGCCTGGAACAGCAGCACAGGCCAGATGCTGAGGGA TAAGTTGAAAGAG CAAAATTTCCAACAAAAGGTGGTAGATGGCCTGGCCTCTGGCATTAGCGGGGTGGTGGAC CTGGCCAACCAGG CAGTGCAAAATAAGATTAACAGTAAGCTTGATCCCCGCCCTCCCGTAGAGGAGCCTCCAC CGGCCGTGGAGAC AGTGTCTCCAGAGGGGCGTGGCGAAAAGCGTCCGCGCCCCGACAGGGAAGAAACTCTGGT GACGCAAATAGAC GAGCCTCCCTCGTACGAGGAGGCACTAAAGCAAGGCCTGCCCACCACCCGTCCCATCGCG CCCATGGCTACCG GAGTGCTGGGCCAGCACACACCCGTAACGCTGGACCTGCCTCCCCCCGCCGACACCCAGC AGAAACCTGTGCT GCCAGGCCCGACCGCCGTTGTTGTAACCCGTCCTAGCCGCGCGTCCCTGCGCCGCGCCGC CAGCGGTCCGCGA TCGTTGCGGCCCGTAGCCAGTGGCAACTGGCAAAGCACACTGAACAGCATCGTGGGTCTG GGGGTGCAATCCC TGAAGCGCCGACGATGCTTCTGAATAGCTAACGTGTCGTATGTGTGTCATGTATGCGTCC ATGTCGCCGCCAG AGGAGCTGCTGAGCCGCCGCGCGCCCGCTTTCCAAGATGGCTACCCCTTCGATGATGCCG CAGTGGTCTTACA TGCACATCTCGGGCCAGGACGCCTCGGAGTACCTGAGCCCCGGGCTGGTGCAGTTTGCCC GCGCCACCGAGAC GTACTTCAGCCTGAATAACAAGTTTAGAAACCCCACGGTGGCGCCTACGCACGACGTGAC CACAGACCGGTCC CAGCGTTTGACGCTGCGGTTCATCCCTGTGGACCGTGAGGATACTGCGTACTCGTACAAG GCGCGGTTCACCC TAGCTGTGGGTGATAACCGTGTGCTGGACATGGCTTCCACGTACTTTGACATCCGCGGCG TGCTGGACAGGGG CCCTACTTTTAAGCCCTACTCTGGCACTGCCTACAACGCCCTGGCTCCCAAGGGTGCCCC AAATCCTTGCGAA TGGGATGAAGCTGCTACTGCTCTTGAAATAAACCTAGAAGAAGAGGACGATGACAACGAA GACGAAGTAGACG AGCAAGCTGAGCAGCAAAAAACTCACGTATTTGGGCAGGCGCCTTATTCTGGTATAAATA TTACAAAGGAGGG TATTCAAATAGGTGTCGAAGGTCAAACACCTAAATATGCCGATAAAACATTTCAACCTGA ACCTCAAATAGGA GAATCTCAGTGGTACGAAACTGAAATTAATCATGCAGCTGGGAGAGTCCTTAAAAAGACT ACCCCAATGAAAC CATGTTACGGTTCATATGCAAAACCCACAAATGAAAATGGAGGGCAAGGCATTCTTGTAA AGCAACAAAATGG AAAGCTAGAAAGTCAAGTGGAAATGCAATTTTTCTCAACTACTGAGGCAGCCGCAGGCAA TGGTGATAACTTG ACTCCTAAAGTGGTATTGTACAGTGAAGATGTAGATATAGAAACCCCAGACACTCATATT TCTTACATGCCCA CTATTAAGGAAGGTAACTCACGAGAACTAATGGGCCAACAATCTATGCCCAACAGGCCTA ATTACATTGCTTT TAGGGACAATTTTATTGGTCTAATGTATTACAACAGCACGGGTAATATGGGTGTTCTGGC GGGCCAAGCATCG CAGTTGAATGCTGTTGTAGATTTGCAAGACAGAAACACAGAGCTTTCATACCAGCTTTTG CTTGATTCCATTG GTGATAGAACCAGGTACTTTTCTATGTGGAATCAGGCTGTTGACAGCTATGATCCAGATG TTAGAATTATTGA AAAT CAT GGAAC T GAAGAT GAAC T TCCAAA AC GC T CC AC GGGAGG G GAT T AAT AC AGAGAC T C T T ACCAAGGT AAAACC T AAAAC AGGT C AGGAAAAT GGAT GGGAAAAAGAT GC T AC AGAAT T T T C AGAT AAAAAT G AAATAAGAGTTGGAAATAATTTTGCCATGGAAATCAATCTAAATGCCAACCTGTGGAGAA ATTTCCTGTACTC CAACATAGCGCTGTATTTGCCCGACAAGCTAAAGTACAGTCCTTCCAACGTAAAAATTTC TGATAACCCAAAC ACCTACGACTACATGAACAAGCGAGTGGTGGCTCCCGGGTTAGTGGACTGCTACATTAAC CTTGGAGCACGCT GGTCCCTTGACTATATGGACAACGTCAACCCATTTAACCACCACCGCAATGCTGGCCTGC GCTACCGCTCAAT GTTGCTGGGCAATGGTCGCTATGTGCCCTTCCACATCCAGGTGCCTCAGAAGTTCTTTGC CATTAAAAACCTC CTTCTCCTGCCGGGCTCATACACCTACGAGTGGAACTTCAGGAAGGATGTTAACATGGTT CTGCAGAGCTCCC TAGGAAATGACCTAAGGGTTGACGGAGCCAGCATTAAGTTTGATAGCATTTGCCTTTACG CCACCTTCTTCCC CATGGCCCACAACACCGCCTCCACGCTTGAGGCCATGCTTAGAAACGACACCAACGACCA GTCCTTTAACGAC TATCTCTCCGCCGCCAACATGCTCTACCCTATACCCGCCAACGCTACCAACGTGCCCATA TCCATCCCCTCCC GCAACTGGGCGGCTTTCCGCGGCTGGGCCTTCACGCGCCTTAAGACTAAGGAAACCCCAT CACTGGGCTCGGG CTACGACCCTTATTACACCTACTCTGGCTCTATACCCTACCTAGATGGAACCTTTTACCT CAACCACACCTTT AAGAAGGTGGCCATTACCTTTGACTCTTCTGTCAGCTGGCCTGGCAATGACCGCCTGCTT ACCCCCAACGAGT TTGAAATTAAGCGCTCAGTTGACGGGGAGGGTTACAACGTTGCCCAGTGTAACATGACCA AAGACTGGTTCCT GGTACAAATGCTAGCTAACTACAACATTGGCTACCAGGGCTTCTATATCCCAGAGAGCTA CAAGGACCGCATG TACTCCTTCTTTAGAAACTTCCAGCCCATGAGCCGTCAGGTGGTGGATGATACTAAATAC AAGGACTACCAAC AGGTGGGCATCCTACACCAACACAACAACTCTGGATTTGTTGGCTACCTTGCCCCCACCA TGCGCGAAGGACA GGCCTACCCTGCTAACTTCCCCTATCCGCTTATAGGCAAGACCGCAGTTGACAGCATTAC CCAGAAAAAGTTT CTTTGCGATCGCACCCTTTGGCGCATCCCATTCTCCAGTAACTTTATGTCCATGGGCGCA CTCACAGACCTGG GCCAAAACCTTCTCTACGCCAACTCCGCCCACGCGCTAGACATGACTTTTGAGGTGGATC CCATGGACGAGCC CACCCTTCTTTATGTTTTGTTTGAAGTCTTTGACGTGGTCCGTGTGCACCGGCCGCACCG CGGCGTCATCGAA ACCGTGTACCTGCGCACGCCCTTCTCGGCCGGCAACGCCACAACATAAAGAAGCAAGCAA CATCAACAACAGC TGCCGCCATGGGCTCCAGTGAGCAGGAACTGAAAGCCATTGTCAAAGATCTTGGTTGTGG GCCATATTTTTTG GGCACCTATGACAAGCGCTTTCCAGGCTTTGTTTCTCCACACAAGCTCGCCTGCGCCATA GTCAATACGGCCG GTCGCGAGACTGGGGGCGTACACTGGATGGCCTTTGCCTGGAACCCGCACTCAAAAACAT GCTACCTCTTTGA GCCCTTTGGCTTTTCTGACCAGCGACTCAAGCAGGTTTACCAGTTTGAGTACGAGTCACT CCTGCGCCGTAGC GCCATTGCTTCTTCCCCCGACCGCTGTATAACGCTGGAAAAGTCCACCCAAAGCGTACAG GGGCCCAACTCGG CCGCCTGTGGACTATTCTGCTGCATGTTTCTCCACGCCTTTGCCAACTGGCCCCAAACTC CCATGGATCACAA CCCCACCATGAACCTTATTACCGGGGTACCCAACTCCATGCTCAACAGTCCCCAGGTACA GCCCACCCTGCGT CGCAACCAGGAACAGCTCTACAGCTTCCTGGAGCGCCACTCGCCCTACTTCCGCAGCCAC AGTGCGCAGATTA GGAGCGCCACTTCTTTTTGTCACTTGAAAAACATGTAAAAATAATGTACTAGAGACACTT TCAATAAAGGCAA ATGCTTTTATTTGTACACTCTCGGGTGATTATTTACCCCCACCCTTGCCGTCTGCGCCGT TTAAAAATCAAAG GGGTTCTGCCGCGCATCGCTATGCGCCACTGGCAGGGACACGTTGCGATACTGGTGTTTA GTGCTCCACTTAA ACTCAGGCACAACCATCCGCGGCAGCTCGGTGAAGTTTTCACTCCACAGGCTGCGCACCA TCACCAACGCGTT TAGCAGGTCGGGCGCCGATATCTTGAAGTCGCAGTTGGGGCCTCCGCCCTGCGCGCGCGA GTTGCGATACACA GGGTTGCAGCACTGGAACACTATCAGCGCCGGGTGGTGCACGCTGGCCAGCACGCTCTTG TCGGAGATCAGAT CCGCGTCCAGGTCCTCCGCGTTGCTCAGGGCGAACGGAGTCAACTTTGGTAGCTGCCTTC CCAAAAAGGGCGC GTGCCCAGGCTTTGAGTTGCACTCGCACCGTAGTGGCATCAAAAGGTGACCGTGCCCGGT CTGGGCGTTAGGA TACAGCGCCTGCATAAAAGCCTTGATCTGCTTAAAAGCCACCTGAGCCTTTGCGCCTTCA GAGAAGAACATGC CGCAAGACTTGCCGGAAAACTGATTGGCCGGACAGGCCGCGTCGTGCACGCAGCACCTTG CGTCGGTGTTGGA GATCTGCACCACATTTCGGCCCCACCGGTTCTTCACGATCTTGGCCTTGCTAGACTGCTC CTTCAGCGCGCGC TGCCCGTTTTCGCTCGTCACATCCATTTCAATCACGTGCTCCTTATTTATCATAATGCTT CCGTGTAGACACT TAAGCTCGCCTTCGATCTCAGCGCAGCGGTGCAGCCACAACGCGCAGCCCGTGGGCTCGT GATGCTTGTAGGT CACCTCTGCAAACGACTGCAGGTACGCCTGCAGGAATCGCCCCATCATCGTCACAAAGGT CTTGTTGCTGGTG AAGGTCAGCTGCAACCCGCGGTGCTCCTCGTTCAGCCAGGTCTTGCATACGGCCGCCAGA GCTTCCACTTGGT CAGGCAGTAGTTTGAAGTTCGCCTTTAGATCGTTATCCACGTGGTACTTGTCCATCAGCG CGCGCGCAGCCTC CATGCCCTTCTCCCACGCAGACACGATCGGCACACTCAGCGGGTTCATCACCGTAATTTC ACTTTCCGCTTCG CTGGGCTCTTCCTCTTCCTCTTGCGTCCGCATACCACGCGCCACTGGGTCGTCTTCATTC AGCCGCCGCACTG TGCGCTTACCTCCTTTGCCATGCTTGATTAGCACCGGTGGGTTGCTGAAACCCACCATTT GTAGCGCCACATC TTCTCTTTCTTCCTCGCTGTCCACGATTACCTCTGGTGATGGCGGGCGCTCGGGCTTGGG AGAAGGGCGCTTC TTTTTCTTCTTGGGCGCAATGGCCAAATCCGCCGCCGAGGTCGATGGCCGCGGGCTGGGT GTGCGCGGCACCA GCGCGTCTTGTGATGAGTCTTCCTCGTCCTCGGACTCGATACGCCGCCTCATCCGCTTTT TTGGGGGCGCCCG GGGAGGCGGCGGCGACGGGGACGGGGACGACACGTCCTCCATGGTTGGGGGACGTCGCGC CGCACCGCGTCCG CGCTCGGGGGTGGTTTCGCGCTGCTCCTCTTCCCGACTGGCCATTTCCTTCTCCTATAGG CAGAAAAAGATCA TGGAGTCAGTCGAGAAGAAGGACAGCCTAACCGCCCCCTCTGAGTTCGCCACCACCGCCT CCACCGATGCCGC CAACGCGCCTACCACCTTCCCCGTCGAGGCACCCCCGCTTGAGGAGGAGGAAGTGATTAT CGAGCAGGACCCA GGTTTTGTAAGCGAAGACGACGAGGACCGCTCAGTACCAACAGAGGATAAAAAGCAAGAC CAGGACAACGCAG AGGCAAACGAGGAACAAGTCGGGCGGGGGGACGAAAGGCATGGCGACTACCTAGATGTGG GAGACGACGTGCT GTTGAAGCATCTGCAGCGCCAGTGCGCCATTATCTGCGACGCGTTGCAAGAGCGCAGCGA TGTGCCCCTCGCC ATAGCGGATGTCAGCCTTGCCTACGAACGCCACCTATTCTCACCGCGCGTACCCCCCAAA CGCCAAGAAAACG GCACATGCGAGCCCAACCCGCGCCTCAACTTCTACCCCGTATTTGCCGTGCCAGAGGTGC TTGCCACCTATCA CATCTTTTTCCAAAACTGCAAGATACCCCTATCCTGCCGTGCCAACCGCAGCCGAGCGGA CAAGCAGCTGGCC TTGCGGCAGGGCGCTGTCATACCTGATATCGCCTCGCTCAACGAAGTGCCAAAAATCTTT GAGGGTCTTGGAC GCGACGAGAAGCGCGCGGCAAACGCTCTGCAACAGGAAAACAGCGAAAATGAAAGTCACT CTGGAGTGTTGGT GGAACTCGAGGGTGACAACGCGCGCCTAGCCGTACTAAAACGCAGCATCGAGGTCACCCA CTTTGCCTACCCG GCACTTAACCTACCCCCCAAGGTCATGAGCACAGTCATGAGTGAGCTGATCGTGCGCCGT GCGCAGCCCCTGG AGAGGGATGCAAATTTGCAAGAACAAACAGAGGAGGGCCTACCCGCAGTTGGCGACGAGC AGCTAGCGCGCTG GCTTCAAACGCGCGAGCCTGCCGACTTGGAGGAGCGACGCAAACTAATGATGGCCGCAGT GCTCGTTACCGTG GAGCTTGAGTGCATGCAGCGGTTCTTTGCTGACCCGGAGATGCAGCGCAAGCTAGAGGAA ACATTGCACTACA CCTTTCGACAGGGCTACGTACGCCAGGCCTGCAAGATCTCCAACGTGGAGCTCTGCAACC TGGTCTCCTACCT TGGAATTTTGCACGAAAACCGCCTTGGGCAAAACGTGCTTCATTCCACGCTCAAGGGCGA GGCGCGCCGCGAC TACGTCCGCGACTGCGTTTACTTATTTCTATGCTACACCTGGCAGACGGCCATGGGCGTT TGGCAGCAGTGCT TGGAGGAGTGCAACCTCAAGGAGCTGCAGAAACTGCTAAAGCAAAACTTGAAGGACCTAT GGACGGCCTTCAA CGAGCGCTCCGTGGCCGCGCACCTGGCGGACATCATTTTCCCCGAACGCCTGCTTAAAAC CCTGCAACAGGGT CTGCCAGACTTCACCAGTCAAAGCATGTTGCAGAACTTTAGGAACTTTATCCTAGAGCGC TCAGGAATCTTGC CCGCCACCTGCTGTGCACTTCCTAGCGACTTTGTGCCCATTAAGTACCGCGAATGCCCTC CGCCGCTTTGGGG CCACTGCTACCTTCTGCAGCTAGCCAACTACCTTGCCTACCACTCTGACATAATGGAAGA CGTGAGCGGTGAC GGTCTACTGGAGTGTCACTGTCGCTGCAACCTATGCACCCCGCACCGCTCCCTGGTTTGC AATTCGCAGCTGC TTAACGAAAGTCAAATTATCGGTACCTTTGAGCTGCAGGGTCCCTCGCCTGACGAAAAGT CCGCGGCTCCGGG GTTGAAACTCACTCCGGGGCTGTGGACGTCGGCTTACCTTCGCAAATTTGTACCTGAGGA CTACCACGCCCAC GAGATTAGGTTCTACGAAGACCAATCCCGCCCGCCAAATGCGGAGCTTACCGCCTGCGTC ATTACCCAGGGCC ACATTCTTGGCCAATTGCAAGCCATCAACAAAGCCCGCCAAGAGTTTCTGCTACGAAAGG GACGGGGGGTTTA CTTGGACCCCCAGTCCGGCGAGGAGCTCAACCCAATCCCCCCGCCGCCGCAGCCCTATCA GCAGCAGCCGCGG GCCCTTGCTTCCCAGGATGGCACCCAAAAAGAAGCTGCAGCTGCCGCCGCCACCCACGGA CGAGGAGGAATAC TGGGACAGTCAGGCAGAGGAGGTTTTGGACGAGGAGGAGGAGGACATGATGGAAGACTGG GAGAGCCTAGACG AGGAAGCTTCCGAGGTCGAAGAGGTGTCAGACGAAACACCGTCACCCTCGGTCGCATTCC CCTCGCCGGCGCC CCAGAAATCGGCAACCGGTTCCAGCATGGCTACAACCTCCGCTCCTCAGGCGCCGCCGGC ACTGCCCGTTCGC CGACCCAACCGTAGATGGGACACCACTGGAACCAGGGCCGGTAAGTCCAAGCAGCCGCCG CCGTTAGCCCAAG AGCAACAACAGCGCCAAGGCTACCGCTCATGGCGCGGGCACAAGAACGCCATAGTTGCTT GCTTGCAAGACTG TGGGGGCAACATCTCCTTCGCCCGCCGCTTTCTTCTCTACCATCACGGCGTGGCCTTCCC CCGTAACATCCTG CATTACTACCGTCATCTCTACAGCCCATACTGCACCGGCGGCAGCGGCAGCGGCAGCAAC AGCAGCGGCCACA CAGAAGCAAAGGCGACCGGATAGCAAGACTCTGACAAAGCCCAAGAAATCCACAGCGGCG GCAGCAGCAGGAG GAGGAGCGCTGCGTCTGGCGCCCAACGAACCCGTATCGACCCGCGAGCTTAGAAACAGGA TTTTTCCCACTCT GTATGCTATATTTCAACAGAGCAGGGGCCAAGAACAAGAGCTGAAAATAAAAAACAGGTC TCTGCGATCCCTC ACCCGCAGCTGCCTGTATCACAAAAGCGAAGATCAGCTTCGGCGCACGCTGGAAGACGCG GAGGCTCTCTTCA GTAAATACTGCGCGCTGACTCTTAAGGACTAGTTTCGCGCCCTTTCTCAAATTTAAGCGC GAAAACTACGTCA TCTCCAGCGGCCACACCCGGCGCCAGCACCTGTCGTCAGCGCCATTATGAGCAAGGAAAT TCCCACGCCCTAC ATGTGGAGTTACCAGCCACAAATGGGACTTGCGGCTGGAGCTGCCCAAGACTACTCAACC CGAATAAACTACA TGAGCGCGGGACCCCACATGATATCCCGGGTCAACGGAATCCGCGCCCACCGAAACCGAA TTCTCTTGGAACA GGCGGCTATTACCACCACACCTCGTAATAACCTTAATCCCCGTAGTTGGCCCGCTGCCCT GGTGTACCAGGAA AGTCCCGCTCCCACCACTGTGGTACTTCCCAGAGACGCCCAGGCCGAAGTTCAGATGACT AACTCAGGGGCGC AGCTTGCGGGCGGCTTTCGTCACAGGGTGCGGTCGCCCGGGCAGGGTATAACTCACCTGA CAATCAGAGGGCG AGGTATTCAGCTCAACGACGAGTCGGTGAGCTCCTCGCTTGGTCTCCGTCCGGACGGGAC ATTTCAGATCGGC GGCGCCGGCCGTCCTTCATTCACGCCTCGTCAGGCAATCCTAACTCTGCAGACCTCGTCC TCTGAGCCGCGCT CTGGAGGCATTGGAACTCTGCAATTTATTGAGGAGTTTGTGCCATCGGTCTACTTTAACC CCTTCTCGGGACC TCCCGGCCACTATCCGGATCAATTTATTCCTAACTTTGACGCGGTAAAGGACTCGGCGGA CGGCTACGACTGA ATGTTAAGTGGAGAGGCAGAGCAACTGCGCCTGAAACACCTGGTCCACTGTCGCCGCCAC AAGTGCTTTGCCC GCGACTCCGGTGAGTTTTGCTACTTTGAATTGCCCGAGGATCATATCGAGGGCCCGGCGC ACGGCGTCCGGCT TACCGCCCAGGGAGAGCTTGCCCGTAGCCTGATTCGGGAGTTTACCCAGCGCCCCCTGCT AGTTGAGCGGGAC AGGGGACCCTGTGTTCTCACTGTGATTTGCAACTGTCCTAACCTTGGATTACATCAAGAT CTTTGTTGCCATC TCTGTGCTGAGTATAATAAATACAGAAATTAAAATATACTGGGGCTCCTATCGCCATCCT GTAAACGCCACCG TCTTCACCCGCCCAAGCAAACCAAGGCGAACCTTACCTGGTACTTTTAACATCTCTCCCT CTGTGATTTACAA CAGTTTCAACCCAGACGGAGTGAGTCTACGAGAGAACCTCTCCGAGCTCAGCTACTCCAT CAGAAAAAACACC ACCCTCCTTACCTGCCGGGAACGTACGAGTGCGTCACCGGCCGCTGCACCACACCTACCG CCTGACCGTAAAC CAGACTTTTTCCGGACAGACCTCAATAACTCTGTTTACCAGAACAGGAGGTGAGCTTAGA AAACCCTTAGGGT ATTAGGCCAAAGGCGCAGCTACTGTGGGGTTTATGAACAATTCAAGCAACTCTACGGGCT ATTCTAATTCAGG TTTCTCTAGAATCGGGGTTGGGGTTATTCTCTGTCTTGTGATTCTCTTTATTCTTATACT AACGCTTCTCTGC CTAAGGCTCGCCGCCTGCTGTGTGCACATTTGCATTTATTGTCAGCTTTTTAAACGCTGG GGTCGCCACCCAA GATGATTAGGTACATAATCCTAGGTTTACTCACCCTTGCGTCAGCCCACGGTACCACCCA AAAGGTGGATTTT AAGGAGCCAGCCTGTAATGTTACATTCGCAGCTGAAGCTAATGAGTGCACCACTCTTATA AAATGCACCACAG AACATGAAAAGCTGCTTATTCGCCACAAAAACAAAATTGGCAAGTATGCTGTTTATGCTA TTTGGCAGCCAGG TGACACTACAGAGTATAATGTTACAGTTTTCCAGGGTAAAAGTCATAAAACTTTTATGTA TACTTTTCCATTT TATGAAATGTGCGACATTACCATGTACATGAGCAAACAGTATAAGTTGTGGCCCCCACAA AATTGTGTGGAAA ACACTGGCACTTTCTGCTGCACTGCTATGCTAATTACAGTGCTCGCTTTGGTCTGTACCC TACTCTATATTAA ATACAAAAGCAGACGCAGCTTTATTGAGGAAAAGAAAATGCCTTAATTTACTAAGTTACA AAGCTAATGTCAC CACTAACTGCTTTACTCGCTGCTTGCAAAACAAATTCAAAAAGTTAGCATTATAATTAGA ATAGGATTTAAAC CCCCCGGTCATTTCCTGCTCAATACCATTCCCCTGAACAATTGACTCTATGTGGGATATG CTCCAGCGCTACA ACCTTGAAGTCAGGCTTCCTGGATGTCAGCATCTGACTTTGGCCAGCACCTGTCCCGCGG ATTTGTTCCAGTC CAACTACAGCGACCCACCCTAACAGAGATGACCAACACAACCAACGCGGCCGCCGCTACC GGACTTACATCTA CCACAAATACACCCCAAGTTTCTGCCTTTGTCAATAACTGGGATAACTTGGGCATGTGGT GGTTCTCCATAGC GCTTATGTTTGTATGCCTTATTATTATGTGGCTCATCTGCTGCCTAAAGCGCAAACGCGC CCGACCACCCATC TATAGTCCCATCATTGTGCTACACCCAAACAATGATGGAATCCATAGATTGGACGGACTG AAACACATGTTCT TTTCTCTTACAGTATGATTAAATGAGACATGATTCCTCGAGTTTTTATATTACTGACCCT TGTTGCGCTTTTT TGTGCGTGCTCCACATTGGCTGCGGTTTCTCACATCGAAGTAGACTGCATTCCAGCCTTC ACAGTCTATTTGC TTTACGGATTTGTCACCCTCACGCTCATCTGCAGCCTCATCACTGTGGTCATCGCCTTTA TCCAGTGCATTGA CTGGGTCTGTGTGCGCTTTGCATATCTCAGACACCATCCCCAGTACAGGGACAGGACTAT AGCTGAGCTTCTT AGAATTCTTTAATTATGAAATTTACTGTGACTTTTCTGCTGATTATTTGCACCCTATCTG CGTTTTGTTCCCC GACCTCCAAGCCTCAAAGACATATATCATGCAGATTCACTCGTATATGGAATATTCCAAG TTGCTACAATGAA AAAAGCGATCTTTCCGAAGCCTGGTTATATGCAATCATCTCTGTTATGGTGTTCTGCAGT ACCATCTTAGCCC TAGCTATATATCCCTACCTTGACATTGGCTGGAAACGAATAGATGCCATGAACCACCCAA CTTTCCCCGCGCC CGCTATGCTTCCACTGCAACAAGTTGTTGCCGGCGGCTTTGTCCCAGCCAATCAGCCTCG CCCCACTTCTCCC ACCCCCACTGAAATCAGCTACTTTAATCTAACAGGAGGAGATGACTGACACCCTAGATCT AGAAATGGACGGA ATTATTACAGAGCAGCGCCTGCTAGAAAGACGCAGGGCAGCGGCCGAGCAACAGCGCATG AATCAAGAGCTCC AAGACATGGTTAACTTGCACCAGTGCAAAAGGGGTATCTTTTGTCTGGTAAAGCAGGCCA AAGTCACCTACGA CAGTAATACCACCGGACACCGCCTTAGCTACAAGTTGCCAACCAAGCGTCAGAAATTGGT GGTCATGGTGGGA GAAAAGCCCATTACCATAACTCAGCACTCGGTAGAAACCGAAGGCTGCATTCACTCACCT TGTCAAGGACCTG AGGATCTCTGCACCCTTATTAAGACCCTGTGCGGTCTCAAAGATCTTATTCCCTTTAACT AATAAAAAAAAAT AATAAAGCATCACTTACTTAAAATCAGTTAGCAAATTTCTGTCCAGTTTATTCAGCAGCA CCTCCTTGCCCTC CTCCCAGCTCTGGTATTGCAGCTTCCTCCTGGCTGCAAACTTTCTCCACAATCTAAATGG AATGTCAGTTTCC TCCTGTTCCTGTCCATCCGCACCCACTATCTTCATGTTGTTGCAGATGAAGCGCGCAAGA CCGTCTGAAGATA CCTTCAACCCCGTGTATCCATATGACACGGAAACCGGTCCTCCAACTGTGCCTTTTCTTA CTCCTCCCTTTGT ATCCCCCAATGGGTTTCAAGAGAGTCCCCCTGGGGTACTCTCTTTGCGCCTATCCGAACC TCTAGTTACCTCC AATGGCATGCTTGCGCTCAAAATGGGCAACGGCCTCTCTCTGGACGAGGCCGGCAACCTT ACCTCCCAAAATG TAACCACTGTGAGCCCACCTCTCAAAAAAACCAAGTCAAACATAAACCTGGAAATATCTG CACCCCTCACAGT TACCTCAGAAGCCCTAACTGTGGCTGCCGCCGCACCTCTAATGGTCGCGGGCAACACACT CACCATGCAATCA CAGGCCCCGCTAACCGTGCACGACTCCAAACTTAGCATTGCCACCCAAGGACCCCTCACA GTGTCAGAAGGAA AGCTAGCCCTGCAAACATCAGGCCCCCTCACCACCACCGATAGCAGTACCCTTACTATCA CTGCCTCACCCCC T C T AAC T AC T GCC AC TGGTAGCTTGGGCATT GAC T T GAAAGAGCCC AT T T AT AC AC AAAAT GGAAAAC TAGGA CTAAAGTACGGGGCTCCTTTGCATGTAACAGACGACCTAAACACTTTGACCGTAGCAACT GGTCCAGGTGTGA CTATTAATAATACTTCCTTGCAAACTAAAGTTACTGGAGCCTTGGGTTTTGATTCACAAG GCAATATGCAACT TAATGTAGCAGGAGGACTAAGGATTGATTCTCAAAACAGACGCCTTATACTTGATGTTAG TTATCCGTTTGAT GCTCAAAACCAACTAAATCTAAGACTAGGACAGGGCCCTCTTTTTATAAACTCAGCCCAC AACTTGGATATTA ACTACAACAAAGGCCTTTACTTGTTTACAGCTTCAAACAATTCCAAAAAGCTTGAGGTTA ACCTAAGCACTGC CAAGGGGTTGATGTTTGACGCTACAGCCATAGCCATTAATGCAGGAGATGGGCTTGAATT TGGTTCACCTAAT GCACCAAACACAAATCCCCTCAAAACAAAAATTGGCCATGGCCTAGAATTTGATTCAAAC AAGGCTATGGTTC CTAAACTAGGAACTGGCCTTAGTTTTGACAGCACAGGTGCCATTACAGTAGGAAACAAAA ATAATGATAAGCT AACTTTGTGGACCACACCAGCTCCATCTCCTAACTGTAGACTAAATGCAGAGAAAGATGC TAAACTCACTTTG GTCTTAACAAAATGTGGCAGTCAAATACTTGCTACAGTTTCAGTTTTGGCTGTTAAAGGC AGTTTGGCTCCAA TATCTGGAACAGTTCAAAGTGCTCATCTTATTATAAGATTTGACGAAAATGGAGTGCTAC TAAACAATTCCTT CCTGGACCCAGAATATTGGAACTTTAGAAATGGAGATCTTACTGAAGGCACAGCCTATAC AAACGCTGTTGGA TTTATGCCTAACCTATCAGCTTATCCAAAATCTCACGGTAAAACTGCCAAAAGTAACATT GTCAGTCAAGTTT ACTTAAACGGAGACAAAACTAAACCTGTAACACTAACCATTACACTAAACGGTACACAGG AAACAGGAGACAC AACTCCAAGTGCATACTCTATGTCATTTTCATGGGACTGGTCTGGCCACAACTACATTAA TGAAATATTTGCC ACATCCTCTTACACTTTTTCATACATTGCCCAAGAATAAAGAATCGTTTGTGTTATGTTT CAACGTGTTTATT TTTCAATTGCAGAAAATTTCAAGTCATTTTTCATTCAGTAGTATAGCCCCACCACCACAT AGCTTATACAGAT CACCGTACCTTAATCAAACTCACAGAACCCTAGTATTCAACCTGCCACCTCCCTCCCAAC ACACAGAGTACAC AGTCCTTTCTCCCCGGCTGGCCTTAAAAAGCATCATATCATGGGTAACAGACATATTCTT AGGTGTTATATTC CACACGGTTTCCTGTCGAGCCAAACGCTCATCAGTGATATTAATAAACTCCCCGGGCAGC TCACTTAAGTTCA TGTCGCTGTCCAGCTGCTGAGCCACAGGCTGCTGTCCAACTTGCGGTTGCTTAACGGGCG GCGAAGGAGAAGT CCACGCCTACATGGGGGTAGAGTCATAATCGTGCATCAGGATAGGGCGGTGGTGCTGCAG CAGCGCGCGAATA AACTGCTGCCGCCGCCGCTCCGTCCTGCAGGAATACAACATGGCAGTGGTCTCCTCAGCG ATGATTCGCACCG CCCGCAGCATAAGGCGCCTTGTCCTCCGGGCACAGCAGCGCACCCTGATCTCACTTAAAT CAGCACAGTAACT GCAGCACAGCACCACAATATTGTTCAAAATCCCACAGTGCAAGGCGCTGTATCCAAAGCT CATGGCGGGGACC ACAGAACCCACGTGGCCATCATACCACAAGCGCAGGTAGATTAAGTGGCGACCCCTCATA AACACGCTGGACA TAAACATTACCTCTTTTGGCATGTTGTAATTCACCACCTCCCGGTACCATATAAACCTCT GATTAAACATGGC GCCATCCACCACCATCCTAAACCAGCTGGCCAAAACCTGCCCGCCGGCTATACACTGCAG GGAACCGGGACTG GAACAATGACAGTGGAGAGCCCAGGACTCGTAACCATGGATCATCATGCTCGTCATGATA TCAATGTTGGCAC AACACAGGCACACGTGCATACACTTCCTCAGGATTACAAGCTCCTCCCGCGTTAGAACCA TATCCCAGGGAAC AACCCATTCCTGAATCAGCGTAAATCCCACACTGCAGGGAAGACCTCGCACGTAACTCAC GTTGTGCATTGTC AAAGTGTTACATTCGGGCAGCAGCGGATGATCCTCCAGTATGGTAGCGCGGGTTTCTGTC TCAAAAGGAGGTA GACGATCCCTACTGTACGGAGTGCGCCGAGACAACCGAGATCGTGTTGGTCGTAGTGTCA TGCCAAATGGAAC GCCGGACGTAGTCATATTTCCTGAAGCAAAACCAGGTGCGGGCGTGACAAACAGATCTGC GTCTCCGGTCTCG CCGCTTAGATCGCTCTGTGTAGTAGTTGTAGTATATCCACTCTCTCAAAGCATCCAGGCG CCCCCTGGCTTCG GGTTCTATGTAAACTCCTTCATGCGCCGCTGCCCTGATAACATCCACCACCGCAGAATAA GCCACACCCAGCC AACCTACACATTCGTTCTGCGAGTCACACACGGGAGGAGCGGGAAGAGCTGGAAGAACCA TGTTTTTTTTTTT ATTCCAAAAGATTATCCAAAACCTCAAAATGAAGATCTATTAAGTGAACGCGCTCCCCTC CGGTGGCGTGGTC AAACTCTACAGCCAAAGAACAGATAATGGCATTTGTAAGATGTTGCACAATGGCTTCCAA AAGGCAAACGGCC CTCACGTCCAAGTGGACGTAAAGGCTAAACCCTTCAGGGTGAATCTCCTCTATAAACATT CCAGCACCTTCAA CCATGCCCAAATAATTCTCATCTCGCCACCTTCTCAATATATCTCTAAGCAAATCCCGAA TATTAAGTCCGGC CATTGTAAAAATCTGCTCCAGAGCGCCCTCCACCTTCAGCCTCAAGCAGCGAATCATGAT TGCAAAAATTCAG GTTCCTCACAGACCTGTATAAGATTCAAAAGCGGAACATTAACAAAAATACCGCGATCCC GTAGGTCCCTTCG CAGGGCCAGCTGAACATAATCGTGCAGGTCTGCACGGACCAGCGCGGCCACTTCCCCGCC AGGAACCTTGACA AAAGAACCCACACTGATTATGACACGCATACTCGGAGCTATGCTAACCAGCGTAGCCCCG ATGTAAGCTTTGT TGCATGGGCGGCGATATAAAATGCAAGGTGCTGCTCAAAAAATCAGGCAAAGCCTCGCGC AAAAAAGAAAGCA CATCGTAGTCATGCTCATGCAGATAAAGGCAGGTAAGCTCCGGAACCACCACAGAAAAAG ACACCATTTTTCT C T C AAAC AT GT C TGCGGGTTTCT GC AT AAAC AC AAAAT AAAAT AAC AAAAAAAC AT T T AAAC AT T AGAAGCC T GTCTTACAACAGGAAAAACAACCCTTATAAGCATAAGACGGACTACGGCCATGCCGGCGT GACCGTAAAAAAA CTGGTCACCGTGATTAAAAAGCACCACCGACAGCTCCTCGGTCATGTCCGGAGTCATAAT GTAAGACTCGGTA AACACATCAGGTTGATTCATCGGTCAGTGCTAAAAAGCGACCGAAATAGCCCGGGGGAAT ACATACCCGCAGG CGTAGAGACAACATTACAGCCCCCATAGGAGGTATAACAAAATTAATAGGAGAGAAAAAC ACATAAACACCTG AAAAACCCTCCTGCCTAGGCAAAATAGCACCCTCCCGCTCCAGAACAACATACAGCGCTT CACAGCGGCAGCC TAACAGTCAGCCTTACCAGTAAAAAAGAAAACCTATTAAAAAAACACCACTCGACACGGC ACCAGCTCAATCA GTCACAGTGTAAAAAAGGGCCAAGTGCAGAGCGAGTATATATAGGACTAAAAAATGACGT AACGGTTAAAGTC CACAAAAAACACCCAGAAAACCGCACGCGAACCTACGCCCAGAAACGAAAGCCAAAAAAC CCACAACTTCCTC AAATCGTCACTTCCGTTTTCCCACGTTACGTAACTTCCCATTTTAAGAAAACTACAATTC CCAACACATACAA GTTACTCCGCCCTAAAACCTACGTCACCCGCCCCGTTCCCACGCCCCGCGCCACGTCACA AACTCCACCCCCT CATTATCATATTGGCTTCAATCCAAAATAAGGTATATTATTGATGATGATTTAAATGGAT CCATTTAAATCGG TACCCAGCTTTTGTTCCCTTTAGTGAGGGTTAATTGCGCGCTTGGCGTAATCATGGTCAT AGCTGTTTCCTGT GTGAAATTGTTATCCGCTCACAATTCCACACAACATACGAGCCGGAAGCATAAAGTGTAA AGCCTGGGGTGCC TAATGAGTGAGCTAACTCACATTAATTGCGTTGCGCTCACTGCCCGCTTTCCAGTCGGGA AACCTGTCGTGCC AGCTGCATTAATGAATCGGCCAACGCGCGGGGAGAGGCGGTTTGCGTATTGGGCGCTCTT CCGCTTCCTCGCT CACTGACTCGCTGCGCTCGGTCGTTCGGCTGCGGCGAGCGGTATCAGCTCACTCAAAGGC GGTAATACGGTTA TCCACAGAATCAGGGGATAACGCAGGAAAGAACATGTGAGCAAAAGGCCAGCAAAAGGCC AGGAACCGTAAAA AGGCCGCGTTGCTGGCGTTTTTCCATAGGCTCCGCCCCCCTGACGAGCATCACAAAAATC GACGCTCAAGTCA GAGGTGGCGAAACCCGACAGGACTATAAAGATACCAGGCGTTTCCCCCTGGAAGCTCCCT CGTGCGCTCTCCT GTTCCGACCCTGCCGCTTACCGGATACCTGTCCGCCTTTCTCCCTTCGGGAAGCGTGGCG CTTTCTCATAGCT CACGCTGTAGGTATCTCAGTTCGGTGTAGGTCGTTCGCTCCAAGCTGGGCTGTGTGCACG AACCCCCCGTTCA GCCCGACCGCTGCGCCTTATCCGGTAACTATCGTCTTGAGTCCAACCCGGTAAGACACGA CTTATCGCCACTG GCAGCAGCCACTGGTAACAGGATTAGCAGAGCGAGGTATGTAGGCGGTGCTACAGAGTTC TTGAAGTGGTGGC CTAACTACGGCTACACTAGAAGGACAGTATTTGGTATCTGCGCTCTGCTGAAGCCAGTTA CCTTCGGAAAAAG AGTTGGTAGCTCTTGATCCGGCAAACAAACCACCGCTGGTAGCGGTGGTTTTTTTGTTTG CAAGCAGCAGATT ACGCGCAGAAAAAAAGGATCTCAAGAAGATCCTTTGATCTTTTCTACGGGGTCTGACGCT CAGTGGAACGAAA ACTCACGTTAAGGGATTTTGGTCATGAGATTATCAAAAAGGATCTTCACCTAGATCCTTT TAAATTAAAAATG AAGTTTTAAATCAATCTAAAGTATATATGAGTAAACTTGGTCTGACAGTTACCAATGCTT AATCAGTGAGGCA CCTATCTCAGCGATCTGTCTATTTCGTTCATCCATAGTTGCCTGACTCCCCGTCGTGTAG ATAACTACGATAC GGGAGGGCTTACCATCTGGCCCCAGTGCTGCAATGATACCGCGAGACCCACGCTCACCGG CTCCAGATTTATC AGCAATAAACCAGCCAGCCGGAAGGGCCGAGCGCAGAAGTGGTCCTGCAACTTTATCCGC CTCCATCCAGTCT ATTAATTGTTGCCGGGAAGCTAGAGTAAGTAGTTCGCCAGTTAATAGTTTGCGCAACGTT GTTGCCATTGCTA CAGGCATCGTGGTGTCACGCTCGTCGTTTGGTATGGCTTCATTCAGCTCCGGTTCCCAAC GATCAAGGCGAGT TACATGATCCCCCATGTTGTGCAAAAAAGCGGTTAGCTCCTTCGGTCCTCCGATCGTTGT CAGAAGTAAGTTG GCCGCAGTGTTATCACTCATGGTTATGGCAGCACTGCATAATTCTCTTACTGTCATGCCA TCCGTAAGATGCT TTTCTGTGACTGGTGAGTACTCAACCAAGTCATTCTGAGAATAGTGTATGCGGCGACCGA GTTGCTCTTGCCC GGCGTCAATACGGGATAATACCGCGCCACATAGCAGAACTTTAAAAGTGCTCATCATTGG AAAACGTTCTTCG GGGCGAAAACTCTCAAGGATCTTACCGCTGTTGAGATCCAGTTCGATGTAACCCACTCGT GCACCCAACTGAT CTTCAGCATCTTTTACTTTCACCAGCGTTTCTGGGTGAGCAAAAACAGGAAGGCAAAATG CCGCAAAAAAGGG AATAAGGGCGACACGGAAATGTTGAATACTCATACTCTTCCTTTTTCAATATTATTGAAG CATTTATCAGGGT TATTGTCTCATGAGCGGATACATATTTGAATGTATTTAGAAAAATAAACAAATAGGGGTT CCGCGCACATTTC CCCGAAAAGTGCCACCTAAATTGTAAGCGTTAATATTTTGTTAAAATTCGCGTTAAATTT TTGTTAAATCAGC TCATTTTTTAACCAATAGGCCGAAATCGGCAAAATCCCTTATAAATCAAAAGAATAGACC GAGATAGGGTTGA GTGTTGTTCCAGTTTGGAACAAGAGTCCACTATTAAAGAACGTGGACTCCAACGTCAAAG GGCGAAAAACCGT CTATCAGGGCGATGGCCCACTACGTGAACCATCACCCTAATCAAGTTTTTTGGGGTCGAG GTGCCGTAAAGCA CTAAATCGGAACCCTAAAGGGAGCCCCCGATTTAGAGCTTGACGGGGAAAGCCGGCGAAC GTGGCGAGAAAGG AAGGGAAGAAAGCGAAAGGAGCGGGCGCTAGGGCGCTGGCAAGTGTAGCGGTCACGCTGC GCGTAACCACCAC ACCCGCCGCGCTTAATGCGCCGCTACAGGGCGCGTCCCATTCGCCATTCAGGCTGCGCAA CTGTTGGGAAGGG CGATCGGTGCGGGCCTCTTCGCTATTACGCCAGCTGGCGAAAGGGGGATGTGCTGCAAGG CGATTAAGTTGGG TAACGCCAGGGTTTTCCCAGTCACGACGTTGTAAAACGACGGCCAGTGAGCGCGCGTAAT ACGACTCACTATA GGGCGAATTGGAGCTCCAC SEQ ID NO: 6 (pBSK-CMV-TPLIn-100K)

cacctaaattgtaagcgttaatattttgttaaaattcgcgttaaatttttgttaaat cageteattttttaaccaatagg ccgaaatcggcaaaatcccttataaatcaaaagaatagaccgagatagggttgagtgttg ttccagtttggaacaagagt ccactattaaagaacgtggactccaacgtcaaagggcgaaaaaccgtctatcagggcgat ggcccactacgtgaaccatc accctaatcaagttttttggggtcgaggtgccgtaaagcactaaatcggaaccctaaagg gagcccccgatttagagctt gacggggaaagccggcgaacgtggcgagaaaggaagggaagaaagcgaaaggagcgggcg ctagggcgctggcaagtgta gcggtcacgctgcgcgtaaccaccacacccgccgcgcttaatgcgccgctacagggcgcg tcccattcgccattcaggct gcgcaactgttgggaagggcgatcggtgcgggcctcttcgctattacgccagctggcgaa agggggatgtgctgcaaggc gattaagttgggtaacgccagggttttcccagtcacgacgttgtaaaacgacggccagtg aattgtaatacgactcacta tagggcgaattgGGTACCatttaaatacgcgtagatcttcaatattggccattagccata ttattcattggttatatagc ataaatcaatattggctattggccattgcatacgttgtatctatatcataatatgtacat ttatattggctcatgtccaa tatgaccgccatgttggcattgattattgactagttattaatagtaatcaattacggggt cattagttcatagcccatat atggagttccgcgttacataacttacggtaaatggcccgcctggctgaccgcccaacgac ccccgcccattgacgtcaat aatgacgtatgttcccatagtaacgccaatagggactttccattgacgtcaatgggtgga gtatttacggtaaactgccc acttggcagtacatcaagtgtatcatatgccaagtccgccccctattgacgtcaatgacg gtaaatggcccgcctggcat tatgcccagtacatgaccttacgggactttectacttggcagtacatctacgtattagtc atcgctattaccatggtgat gcggttttggcagtacaccaatgggcgtggatagcggtttgactcacggggatttccaag tctccaccccattgacgtca atgggagtttgttttggcaccaaaatcaacgggactttccaaaatgtcgtaataaccccg ccccgttgacgcaaatgggc ggtaggcgtgtacggtgggaggtctatataagcaGAGCTCgtttagtgaaccgtcagatc actagaagctTACTCTCTTC CGCATCGCTGTCTGCGAGGGCCAGCTGTTGGGCTCGCGGTTGAGGACAAACTCTTCGCGG TCTTTCCAGTACTCTTGGAT CGGAAACCCGTCGGCCTCCGAACGGTACTCCGCCGCCGAGGGACCTGAGCGAGTCCGCAT CGACCGGATCGGAAAACCTC TCGAGAAAGGCGTCTAACCAGTCACAGTCGCAAGgtaagtatcaaggttacaagacaggt ttaaggagaccaatagaaac tgggcttgtcgagacagagaagactcttgcgtttctgataggcacctattggtcttactg acatccactttgcctttctc tccacaggtGCggccGCgaccATGGAGTCAGTCGAGAAGAAGGACAGCCTAACCGCCCCC TCTGAGTTCGCCACCACCGC CTCCACCGATGCCGCCAACGCGCCTACCACCTTCCCCGTCGAGGCACCCCCGCTTGAGGA GGAGGAAGTGATTATCGAGC AGGACCCAGGTTTTGTAAGCGAAGACGACGAGGACCGCTCAGTACCAACAGAGGATAAAA AGCAAGACCAGGACAACGCA GAGGCAAACGAGGAACAAGTCGGGCGGGGGGACGAAAGGCATGGCGACTACCTAGATGTG GGAGACGACGTGCTGTTGAA GCATCTGCAGCGCCAGTGCGCCATTATCTGCGACGCGTTGCAAGAGCGCAGCGATGTGCC CCTCGCCATAGCGGATGTCA GCCTTGCCTACGAACGCCACCTATTCTCACCGCGCGTACCCCCCAAACGCCAAGAAAACG GCACATGCGAGCCCAACCCG CGCCTCAACTTCTACCCCGTATTTGCCGTGCCAGAGGTGCTTGCCACCTATCACATCTTT TTCCAAAACTGCAAGATACC CCTATCCTGCCGTGCCAACCGCAGCCGAGCGGACAAGCAGCTGGCCTTGCGGCAGGGCGC TGTCATACCTGATATCGCCT CGCTCAACGAAGTGCCAAAAATCTTTGAGGGTCTTGGACGCGACGAGAAGCGCGCGGCAA ACGCTCTGCAACAGGAAAAC AGCGAAAATGAAAGTCACTCTGGAGTGTTGGTGGAACTCGAGGGTGACAACGCGCGCCTA GCCGTACTAAAACGCAGCAT CGAGGTCACCCACTTTGCCTACCCGGCACTTAACCTACCCCCCAAGGTCATGAGCACAGT CATGAGTGAGCTGATCGTGC GCCGTGCGCAGCCCCTGGAGAGGGATGCAAATTTGCAAGAACAAACAGAGGAGGGCCTAC CCGCAGTTGGCGACGAGCAG CTAGCGCGCTGGCTTCAAACGCGCGAGCCTGCCGACTTGGAGGAGCGACGCAAACTAATG ATGGCCGCAGTGCTCGTTAC CGTGGAGCTTGAGTGCATGCAGCGGTTCTTTGCTGACCCGGAGATGCAGCGCAAGCTAGA GGAAACATTGCACTACACCT TTCGACAGGGCTACGTACGCCAGGCCTGCAAGATCTCCAACGTGGAGCTCTGCAACCTGG TCTCCTACCTTGGAATTTTG CACGAAAACCGCCTTGGGCAAAACGTGCTTCATTCCACGCTCAAGGGCGAGGCGCGCCGC GACTACGTCCGCGACTGCGT TTACTTATTTCTATGCTACACCTGGCAGACGGCCATGGGCGTTTGGCAGCAGTGCTTGGA GGAGTGCAACCTCAAGGAGC TGCAGAAACTGCTAAAGCAAAACTTGAAGGACCTATGGACGGCCTTCAACGAGCGCTCCG TGGCCGCGCACCTGGCGGAC ATCATTTTCCCCGAACGCCTGCTTAAAACCCTGCAACAGGGTCTGCCAGACTTCACCAGT CAAAGCATGTTGCAGAACTT TAGGAACTTTATCCTAGAGCGCTCAGGAATCTTGCCCGCCACCTGCTGTGCACTTCCTAG CGACTTTGTGCCCATTAAGT ACCGCGAATGCCCTCCGCCGCTTTGGGGCCACTGCTACCTTCTGCAGCTAGCCAACTACC TTGCCTACCACTCTGACATA ATGGAAGACGTGAGCGGTGACGGTCTACTGGAGTGTCACTGTCGCTGCAACCTATGCACC CCGCACCGCTCCCTGGTTTG CAATTCGCAGCTGCTTAACGAAAGTCAAATTATCGGTACCTTTGAGCTGCAGGGTCCCTC GCCTGACGAAAAGTCCGCGG CTCCGGGGTTGAAACTCACTCCGGGGCTGTGGACGTCGGCTTACCTTCGCAAATTTGTAC CTGAGGACTACCACGCCCAC GAGATTAGGTTCTACGAAGACCAATCCCGCCCGCCAAATGCGGAGCTTACCGCCTGCGTC ATTACCCAGGGCCACATTCT TGGCCAATTGCAAGCCATCAACAAAGCCCGCCAAGAGTTTCTGCTACGAAAGGGACGGGG GGTTTACTTGGACCCCCAGT CCGGCGAGGAGCTCAACCCAATCCCCCCGCCGCCGCAGCCCTATCAGCAGCAGCCGCGGG CCCTTGCTTCCCAGGATGGC ACCCAAAAAGAAGCTGCAGCTGCCGCCGCCACCCACGGACGAGGAGGAATACTGGGACAG TCAGGCAGAGGAGGTTTTGG ACGAGGAGGAGGAGGACATGATGGAAGACTGGGAGAGCCTAGACGAGGAAGCTTCCGAGG TCGAAGAGGTGTCAGACGAA ACACCGTCACCCTCGGTCGCATTCCCCTCGCCGGCGCCCCAGAAATCGGCAACCGGTTCC AGCATGGCTACAACCTCCGC TCCTCAGGCGCCGCCGGCACTGCCCGTTCGCCGACCCAACCGTAGCCCGGGaatatcggc cgcttcgagcagacatgata agatacattgatgagtttggacaaaccacaactagaatgcagtgaaaaaaatgctttatt tgtgaaatttgtgatgctat tgctttatttgtaaccattataagctgcaataaacaagttaacaacaacaattgcattca ttttatgtttcaggttcagg gggagatgtgggaggttttttaaagcaagtaaaacctctacaaatgtggtaaaatcgata aggatctgcGGCCggccgca tttaaatAGCTCcagcttttgttccctttagtgagggttaatttcgagcttggcgtaatc atggtcatagctgtttcctg tgtgaaattgttatccgctcacaattccacacaacatacgagccggaagcataaagtgta aagcctggggtgcctaatga gtgagctaactcacattaattgcgttgcgctcactgcccgctttccagtcgggaaacctg tcgtgccagctgcattaatg aatcggccaacgcgcggggagaggcggtttgcgtattgggcgctcttccgcttcctcgct cactgactcgctgcgctcgg tcgttcggctgcggcgagcggtatcagctcactcaaaggcggtaatacggttatccacag aatcaggggataacgcagga aagaacatgtgagcaaaaggccagcaaaaggccaggaaccgtaaaaaggccgcgttgctg gcgtttttccataggctccg cccccctgacgagcatcacaaaaatcgacgctcaagtcagaggtggcgaaacccgacagg actataaagataccaggcgt ttccccctggaagctccctcgtgcgctctcctgttccgaccctgccgcttaccggatacc tgtccgcctttctcccttcg ggaagcgtggcgctttctcatagctcacgctgtaggtatctcagttcggtgtaggtcgtt cgctccaagctgggctgtgt gcacgaaccccccgttcagcccgaccgctgcgccttatccggtaactatcgtcttgagtc caacccggtaagacacgact tatcgccactggcagcagccactggtaacaggattagcagagcgaggtatgtaggcggtg ctacagagttcttgaagtgg tggcctaactacggctacactagaaggacagtatttggtatctgcgctctgctgaagcca gttaccttcggaaaaagagt tggtagctcttgatccggcaaacaaaccaccgctggtagcggtggtttttttgtttgcaa gcagcagattacgcgcagaa aaaaaggatctcaagaagatcctttgatcttttctacggggtctgacgctcagtggaacg aaaactcacgttaagggatt ttggtcatgagattatcaaaaaggatcttcacctagatccttttaaattaaaaatgaagt tttaaatcaatctaaagtat atatgagtaaacttggtctgacagttaccaatgcttaatcagtgaggcacctatctcagc gatctgtctatttcgttcat ccatagttgcctgactccccgtcgtgtagataactacgatacgggagggcttaccatctg gccccagtgctgcaatgata ccgcgagacccacgctcaccggctccagatttatcagcaataaaccagccagccggaagg gccgagcgcagaagtggtcc tgcaactttatccgcctccatccagtctattaattgttgccgggaagctagagtaagtag ttcgccagttaatagtttgc gcaacgttgttgccattgctacaggcatcgtggtgtcacgctcgtcgtttggtatggctt cattcagctccggttcccaa cgatcaaggcgagttacatgatcccccatgttgtgcaaaaaagcggttagctccttcggt cctccgatcgttgtcagaag taagttggccgcagtgttatcactcatggttatggcagcactgcataattctcttactgt catgccatccgtaagatgct tttctgtgactggtgagtactcaaccaagtcattctgagaatagtgtatgcggcgaccga gttgctcttgcccggcgtca atacgggataataccgcgccacatagcagaactttaaaagtgctcatcattggaaaacgt tcttcggggcgaaaactctc aaggatcttaccgctgttgagatccagttcgatgtaacccactcgtgcacccaactgatc ttcagcatcttttactttca ccagcgtttctgggtgagcaaaaacaggaaggcaaaatgccgcaaaaaagggaataaggg cgacacggaaatgttgaata ctcatactcttcctttttcaatattattgaagcatttatcagggttattgtctcatgagc ggatacatatttgaatgtat ttagaaaaataaacaaataggggttccgcgcacatttccccgaaaagtgc

SEQ ID NO: 7 (Bacmid Ad5A100K)

ATTATTATAGTCAGCTGACGTGTAGTGTATTTATACCCGGTGAGTTCCTCAAGAGGCCAC TCTTGAGTGCCAGCGAGTAG AGTTTTCTCCTCCGAGCCGCTCCGACACCGGGACTGAAAATGAGACATATTATCTGCCAC GGAGGTGTTATTACCGAAGA AATGGCCGCCAGTCTTTTGGACCAGCTGATCGAAGAGGTACTGGCTGATAATCTTCCACC TCCTAGCCATTTTGAACCAC CTACCCTTCACGAACTGTATGATTTAGACGTGACGGCCCCCGAAGATCCCAACGAGGAGG CGGTTTCGCAGATTTTTCCC GACTCTGTAATGTTGGCGGTGCAGGAAGGGATTGACTTACTCACTTTTCCGCCGGCGCCC GGTTCTCCGGAGCCGCCTCA CCTTTCCCGGCAGCCCGAGCAGCCGGAGCAGAGAGCCTTGGGTCCGGTTTCTATGCCAAA CCTTGTACCGGAGGTGATCG ATCTTACCTGCCACGAGGCTGGCTTTCCACCCAGTGACGACGAGGATGAAGAGGGTGAGG AGTTTGTGTTAGATTATGTG GAGCACCCCGGGCACGGTTGCAGGTCTTGTCATTATCACCGGAGGAATACGGGGGACCCA GATATTATGTGTTCGCTTTG CTATATGAGGACCTGTGGCATGTTTGTCTACAGTAAGTGAAAATTATGGGCAGTGGGTGA TAGAGTGGTGGGTTTGGTGT GGTAATTTTTTTTTTAATTTTTACAGTTTTGTGGTTTAAAGAATTTTGTATTGTGATTTT TTTAAAAGGTCCTGTGTCTG AACCTGAGCCTGAGCCCGAGCCAGAACCGGAGCCTGCAAGACCTACCCGCCGTCCTAAAA TGGCGCCTGCTATCCTGAGA CGCCCGACATCACCTGTGTCTAGAGAATGCAATAGTAGTACGGATAGCTGTGACTCCGGT CCTTCTAACACACCTCCTGA GATACACCCGGTGGTCCCGCTGTGCCCCATTAAACCAGTTGCCGTGAGAGTTGGTGGGCG TCGCCAGGCTGTGGAATGTA TCGAGGACTTGCTTAACGAGCCTGGGCAACCTTTGGACTTGAGCTGTAAACGCCCCAGGC CATAAGGTGTAAACCTGTGA TTGCGTGTGTGGTTAACGCCTTTGTTTGCTGAATGAGTTGATGTAAGTTTAATAAAGGGT GAGATAATGTTTAACTTGCA TGGCGTGTTAAATGGGGCGGGGCTTAAAGGGTATATAATGCGCCGTGGGCTAATCTTGGT TACATCTGACCTCATGGAGG CTTGGGAGTGTTTGGAAGATTTTTCTGCTGTGCGTAACTTGCTGGAACAGAGCTCTAACA GTACCTCTTGGTTTTGGAGG TTTCTGTGGGGCTCATCCCAGGCAAAGTTAGTCTGCAGAATTAAGGAGGATTACAAGTGG GAATTTGAAGAGCTTTTGAA ATCCTGTGGTGAGCTGTTTGATTCTTTGAATCTGGGTCACCAGGCGCTTTTCCAAGAGAA GGTCATCAAGACTTTGGATT TTTCCACACCGGGGCGCGCTGCGGCTGCTGTTGCTTTTTTGAGTTTTATAAAGGATAAAT GGAGCGAAGAAACCCATCTG AGCGGGGGGTACCTGCTGGATTTTCTGGCCATGCATCTGTGGAGAGCGGTTGTGAGACAC AAGAATCGCCTGCTACTGTT GTCTTCCGTCCGCCCGGCGATAATACCGACGGAGGAGCAGCAGCAGCAGCAGGAGGAAGC CAGGCGGCGGCGGCAGGAGC AGAGCCCATGGAACCCGAGAGCCGGCCTGGACCCTCGGGAATGAATGTTGTACAGGTGGC TGAACTGTATCCAGAACTGA GACGCATTTTGACAATTACAGAGGATGGGCAGGGGCTAAAGGGGGTAAAGAGGGAGCGGG GGGCTTGTGAGGCTACAGAG GAGGCTAGGAATCTAGCTTTTAGCTTAATGACCAGACACCGTCCTGAGTGTATTACTTTT CAACAGATCAAGGATAATTG CGCTAATGAGCTTGATCTGCTGGCGCAGAAGTATTCCATAGAGCAGCTGACCACTTACTG GCTGCAGCCAGGGGATGATT TTGAGGAGGCTATTAGGGTATATGCAAAGGTGGCACTTAGGCCAGATTGCAAGTACAAGA TCAGCAAACTTGTAAATATC AGGAATTGTTGCTACATTTCTGGGAACGGGGCCGAGGTGGAGATAGATACGGAGGATAGG GTGGCCTTTAGATGTAGCAT GATAAATATGTGGCCGGGGGTGCTTGGCATGGACGGGGTGGTTATTATGAATGTAAGGTT TACTGGCCCCAATTTTAGCG GTACGGTTTTCCTGGCCAATACCAACCTTATCCTACACGGTGTAAGCTTCTATGGGTTTA ACAATACCTGTGTGGAAGCC TGGACCGATGTAAGGGTTCGGGGCTGTGCCTTTTACTGCTGCTGGAAGGGGGTGGTGTGT CGCCCCAAAAGCAGGGCTTC AATTAAGAAATGCCTCTTTGAAAGGTGTACCTTGGGTATCCTGTCTGAGGGTAACTCCAG GGTGCGCCACAATGTGGCCT CCGACTGTGGTTGCTTCATGCTAGTGAAAAGCGTGGCTGTGATTAAGCATAACATGGTAT GTGGCAACTGCGAGGACAGG GCCTCTCAGATGCTGACCTGCTCGGACGGCAACTGTCACCTGCTGAAGACCATTCACGTA GCCAGCCACTCTCGCAAGGC CTGGCCAGTGTTTGAGCATAACATACTGACCCGCTGTTCCTTGCATTTGGGTAACAGGAG GGGGGTGTTCCTACCTTACC AATGCAATTTGAGTCACACTAAGATATTGCTTGAGCCCGAGAGCATGTCCAAGGTGAACC TGAACGGGGTGTTTGACATG ACCATGAAGATCTGGAAGGTGCTGAGGTACGATGAGACCCGCACCAGGTGCAGACCCTGC GAGTGTGGCGGTAAACATAT TAGGAACCAGCCTGTGATGCTGGATGTGACCGAGGAGCTGAGGCCCGATCACTTGGTGCT GGCCTGCACCCGCGCTGAGT TTGGCTCTAGCGATGAAGATACAGATTGAGGTACTGAAATGTGtgggcgtggCttaaggg tgggaaagaatatataaggt gggggtcttatgtagttttgtatctgttttgcagcagccgccgccgccatgagcaccaac tcgtttgatggaagcattgt gagctcatatttgacaacgcgcatgcccccatgggccggggtgcgtcagaatgtgatggg ctccagcattgatggtcgcc ccgtcctgcccgcaaactctactaccttgacctacgagaccgtgtctggaacgccgttgg agactgcagcctccgccgcc gcttcagccgctgcagccaccgcccgcgggattgtgactgactttgctttcctgagcccg cttgcaagcagtgcagcttc ccgttcatccgcccgcgatgacaagttgacggctcttttggcacaattggattctttgac ccgggaacttaatgtcgttt ctcagcagctgttggatctgcgccagcaggtttctgccctgaaggcttcctcccctccca atgcggtttaaaacataaat aaaaaaccagactctgtttggatttggatcaagcaagtgtcttgctgtctttatttaggg gttttgcgcgcgcggtaggc ccgggaccagcggtctcggtcgttgagggtcctgtgtattttttccaggacgtggtaaag gtgactctggatgttcagat acatgggcataagcccgtctctggggtggaggtagcaccactgcagagcttcatgctgcg gggtggtgttgtagatgatc cagtcgtagcaggagcgctgggcgtggtgcctaaaaatgtctttcagtagcaagctgatt gccaggggcaggcccttggt gtaagtgtttacaaagcggttaagctgggatgggtgcatacgtggggatatgagatgcat cttggactgtatttttaggt tggctatgttcccagccatatccctccggggattcatgttgtgcagaaccaccagcacag tgtatccggtgcacttggga aatttgtcatgtagcttagaaggaaatgcgtggaagaacttggagacgcccttgtgacct ccaagattttccatgcattc gtccataatgatggcaatgggcccacgggcggcggcctgggcgaagatatttctgggatc actaacgtcatagttgtgtt ccaggatgagatcgtcataggccatttttacaaagcgcgggcggagggtgccagactgcg gtataatggttccatccggc ccaggggcgtagttaccctcacagatttgcatttcccacgctttgagttcagatgggggg atcatgtctacctgcggggc gatgaagaaaacggtttccggggtaggggagatcagctgggaagaaagcaggttcctgag cagctgcgacttaccgcagc cggtgggcccgtaaatcacacctattaccgggtgcaactggtagttaagagagctgcagc tgccgtcatccctgagcagg ggggccacttcgttaagcatgtccctgactcgcatgttttccctgaccaaatccgccaga aggcgctcgccgcccagcga tagcagttcttgcaaggaagcaaagtttttcaacggtttgagaccgtccgccgtaggcat gcttttgagcgtttgaccaa gcagttccaggcggtcccacagctcggtcacctgctctacggcatctcgatccagcatat ctcctcgtttcgcgggttgg ggcggctttcgctgtacggcagtagtcggtgctcgtccagacgggccagggtcatgtctt tccacgggcgcagggtcctc gtcagcgtagtctgggtcacggtgaaggggtgcgctccgggctgcgcgctggccagggtg cgcttgaggctggtcctgct ggtgctgaagcgctgccggtcttcgccctgcgcgtcggccaggtagcatttgaccatggt gtcatagtccagcccctccg cggcgtggcccttggcgcgcagcttgcccttggaggaggcgccgcacgaggggcagtgca gacttttgagggcgtagagc ttgggcgcgagaaataccgattccggggagtaggcatccgcgccgcaggccccgcagacg gtctcgcattccacgagcca ggtgagctctggccgttcggggtcaaaaaccaggtttcccccatgctttttgatgcgttt cttacctctggtttccatga gccggtgtccacgctcggtgacgaaaaggctgtccgtgtccccgtatacagacttgagag gcctgtcctcgagcggtgtt ccgcggtcctcctcgtatagaaactcggaccactctgagacaaaggctcgcgtccaggcc agcacgaaggaggctaagtg ggaggggtagcggtcgttgtccactagggggtccactcgctccagggtgtgaagacacat gtcgccctcttcggcatcaa ggaaggtgattggtttgtaggtgtaggccacgtgaccgggtgttcctgaaggggggctat aaaagggggtgggggcgcgt tcgtcctcactctcttccgcatcgctgtctgcgagggccagctgttggggtgagtactcc ctctgaaaagcgggcatgac ttctgcgctaagattgtcagtttccaaaaacgaggaggatttgatattcacctggcccgc ggtgatgcctttgagggtgg ccgcatccatctggtcagaaaagacaatctttttgttgtcaagcttggtggcaaacgacc cgtagagggcgttggacagc aacttggcgatggagcgcagggtttggtttttgtcgcgatcggcgcgctccttggccgcg atgtttagctgcacgtattc gcgcgcaacgcaccgccattcgggaaagacggtggtgcgctcgtcgggcaccaggtgcac gcgccaaccgcggttgtgca gggtgacaaggtcaacgctggtggctacctctccgcgtaggcgctcgttggtccagcaga ggcggccgcccttgcgcgag cagaatggcggtagggggtctagctgcgtctcgtccggggggtctgcgtccacggtaaag accccgggcagcaggcgcgc gtcgaagtagtctatcttgcatccttgcaagtctagcgcctgctgccatgcgcgggcggc aagcgcgcgctcgtatgggt tgagtgggggaccccatggcatggggtgggtgagcgcggaggcgtacatgccgcaaatgt cgtaaacgtagaggggctct ctgagtattccaagatatgtagggtagcatcttccaccgcggatgctggcgcgcacgtaa tcgtatagttcgtgcgaggg agcgaggaggtcgggaccgaggttgctacgggcgggctgctctgctcggaagactatctg cctgaagatggcatgtgagt tggatgatatggttggacgctggaagacgttgaagctggcgtctgtgagacctaccgcgt cacgcacgaaggaggcgtag gagtcgcgcagcttgttgaccagctcggcggtgacctgcacgtctagggcgcagtagtcc agggtttccttgatgatgtc atacttatcctgtcccttttttttccacagctcgcggttgaggacaaactcttcgcggtc tttccagtactcttggatcg gaaacccgtcggcctccgaacggtaagagcctagcatgtagaactggttgacggcctggt aggcgcagcatcccttttct acgggtagcgcgtatgcctgcgcggccttccggagcgaggtgtgggtgagcgcaaaggtg tccctgaccatgactttgag gtactggtatttgaagtcagtgtcgtcgcatccgccctgctcccagagcaaaaagtccgt gcgctttttggaacgcggat ttggcagggcgaaggtgacatcgttgaagagtatctttcccgcgcgaggcataaagttgc gtgtgatgcggaagggtccc ggcacctcggaacggttgttaattacctgggcggcgagcacgatctcgtcaaagccgttg atgttgtggcccacaatgta aagttccaagaagcgcgggatgcccttgatggaaggcaattttttaagttcctcgtaggt gagctcttcaggggagctga gcccgtgctctgaaagggcccagtctgcaagatgagggttggaagcgacgaatgagctcc acaggtcacgggccattagc atttgcaggtggtcgcgaaaggtcctaaactggcgacctatggccattttttctggggtg atgcagtagaaggtaagcgg gtcttgttcccagcggtcccatccaaggttcgcggctaggtctcgcgcggcagtcactag aggctcatctccgccgaact tcatgaccagcatgaagggcacgagctgcttcccaaaggcccccatccaagtataggtct ctacatcgtaggtgacaaag agacgctcggtgcgaggatgcgagccgatcgggaagaactggatctcccgccaccaattg gaggagtggctattgatgtg gtgaaagtagaagtccctgcgacgggccgaacactcgtgctggcttttgtaaaaacgtgc gcagtactggcagcggtgca cgggctgtacatcctgcacgaggttgacctgacgaccgcgcacaaggaagcagagtggga atttgagcccctcgcctggc gggtttggctggtggtcttctacttcggctgcttgtccttgaccgtctggctgctcgagg ggagttacggtggatcggac caccacgccgcgcgagcccaaagtccagatgtccgcgcgcggcggtcggagcttgatgac aacatcgcgcagatgggagc tgtccatggtctggagctcccgcggcgtcaggtcaggcgggagctcctgcaggtttacct cgcatagacgggtcagggcg cgggctagatccaggtgatacctaatttccaggggctggttggtggcggcgtcgatggct tgcaagaggccgcatccccg cggcgcgactacggtaccgcgcggcgggcggtgggccgcgggggtgtccttggatgatgc atctaaaagcggtgacgcgg gcgagcccccggaggtagggggggctccggacccgccgggagagggggcaggggcacgtc ggcgccgcgcgcgggcagga gctggtgctgcgcgcgtaggttgctggcgaacgcgacgacgcggcggttgatctcctgaa tctggcgcctctgcgtgaag acgacgggcccggtgagcttgagcctgaaagagagttcgacagaatcaatttcggtgtcg ttgacggcggcctggcgcaa aatctcctgcacgtctcctgagttgtcttgataggcgatctcggccatgaactgctcgat ctcttcctcctggagatctc cgcgtccggctcgctccacggtggcggcgaggtcgttggaaatgcgggccatgagctgcg agaaggcgttgaggcctccc tcgttccagacgcggctgtagaccacgcccccttcggcatcgcgggcgcgcatgaccacc tgcgcgagattgagctccac gtgccgggcgaagacggcgtagtttcgcaggcgctgaaagaggtagttgagggtggtggc ggtgtgttctgccacgaaga agtacataacccagcgtcgcaacgtggattcgttgatatcccccaaggcctcaaggcgct ccatggcctcgtagaagtcc acggcgaagttgaaaaactgggagttgcgcgccgacacggttaactcctcctccagaaga cggatgagctcggcgacagt gtcgcgcacctcgcgctcaaaggctacaggggcctcttcttcttcttcaatctcctcttc cataagggcctccccttctt cttcttctggcggcggtgggggaggggggacacggcggcgacgacggcgcaccgggaggc ggtcgacaaagcgctcgatc atctccccgcggcgacggcgcatggtctcggtgacggcgcggccgttctcgcgggggcgc agttggaagacgccgcccgt catgtcccggttatgggttggcggggggctgccatgcggcagggatacggcgctaacgat gcatctcaacaattgttgtg taggtactccgccgccgagggacctgagcgagtccgcatcgaccggatcggaaaacctct cgagaaaggcgtctaaccag tcacagtcgcaaggtaggctgagcaccgtggcgggcggcagcgggcggcggtcggggttg tttctggcggaggtgctgct gatgatgtaattaaagtaggcggtcttgagacggcggatggtcgacagaagcaccatgtc cttgggtccggcctgctgaa tgcgcaggcggtcggccatgccccaggcttcgttttgacatcggcgcaggtctttgtagt agtcttgcatgagcctttct accggcacttcttcttctccttcctcttgtcctgcatctcttgcatctatcgctgcggcg gcggcggagtttggccgtag gtggcgccctcttcctcccatgcgtgtgaccccgaagcccctcatcggctgaagcagggc taggtcggcgacaacgcgct cggctaatatggcctgctgcacctgcgtgagggtagactggaagtcatccatgtccacaa agcggtggtatgcgcccgtg ttgatggtgtaagtgcagttggccataacggaccagttaacggtctggtgacccggctgc gagagctcggtgtacctgag acgcgagtaagccctcgagtcaaatacgtagtcgttgcaagtccgcaccaggtactggta tcccaccaaaaagtgcggcg gcggctggcggtagaggggccagcgtagggtggccggggctccgggggcgagatcttcca acataaggcgatgatatccg tagatgtacctggacatccaggtgatgccggcggcggtggtggaggcgcgcggaaagtcg cggacgcggttccagatgtt gcgcagcggcaaaaagtgctccatggtcgggacgctctggccggtcaggcgcgcgcaatc gttgacgctctagaccgtgc aaaaggagagcctgtaagcgggcactcttccgtggtctggtggataaattcgcaagggta tcatggcggacgaccggggt tcgagccccgtatccggccgtccgccgtgatccatgcggttaccgcccgcgtgtcgaacc caggtgtgcgacgtcagaca acgggggagtgctccttttggcttccttccaggcgcggcggctgctgcgctagctttttt ggccactggccgcgcgcagc gtaagcggttaggctggaaagcgaaagcattaagtggctcgctccctgtagccggagggt tattttccaagggttgagtc gcgggacccccggttcgagtctcggaccggccggactgcggcgaacgggggtttgcctcc ccgtcatgcaagaccccgct tgcaaattcctccggaaacagggacgagccccttttttgcttttcccagatgcatccggt gctgcggcagatgcgccccc ctcctcagcagcggcaagagcaagagcagcggcagacatgcagggcaccctcccctcctc ctaccgcgtcaggaggggcg acatccgcggttgacgcggcagcagatggtgattacgaacccccgcggcgccgggcccgg cactacctggacttggagga gggcgagggcctggcgcggctaggagcgccctctcctgagcggtacccaagggtgcagct gaagcgtgatacgcgtgagg cgtacgtgccgcggcagaacctgtttcgcgaccgcgagggagaggagcccgaggagatgc gggatcgaaagttccacgca gggcgcgagctgcggcatggcctgaatcgcgagcggttgctgcgcgaggaggactttgag cccgacgcgcgaaccgggat tagtccccgtggcggccgccgacctggtaaccgcatacgagcagacggtgaaccaggaga ttaactttcaagcgcgcgca caaaaagctttaacaaccacgtgcgtacgcttgtggcgcgcgaggaggtggctataggac tgatgcatctgtgggacttt gtaagcgcgctggagcaaaacccaaatagcaagccgctcatggcgcagctgttccttata gtgcagcacagcagggacaa cgaggcattcagggatgcgctgctaaacatagtagagcccgagggccgctggctgctcga tttgataaacatcctgcaga gcatagtggtgcaggagcgcagcttgagcctggctgacaaggtggccgccatcaactatt ccatgcttagcctgggcaag ttttacgcccgcaagatataccataccccttacgttcccatagacaaggaggtaaagatc gaggggttctacatgcgcat ggcgctgaaggtgcttaccttgagcgacgacctgggcgtttatcgcaacgagcgcatcca caaggccgtgagcgtgagcc ggcggcgcgagctcagcgaccgcgagctgatgcacagcctgcaaagggccctggctggca cgggcagcggcgatagagag gccgagtcctactttgacgcgggcgctgacctgcgctgggccccaagccgacgcgccctg gaggcagctggggccggacc tgggctggcggtggcacccgcgcgcgctggcaacgtcggcggcgtggaggaatatgacga ggacgatgagtacgagccag aggacggcgagtactaagcggtgatgtttctgatcagatgatgcaagacgcaacggaccc ggcggtgcgggcggcgctgc agagccagccgtccggccttaactccacggacgactggcgccaggtcatggaccgcatca tgtcgctgactgcgcgcaat cctgacgcgttccggcagcagccgcaggccaaccggctctccgcaattctggaagcggtg gtcccggcgcgcgcaaaccc cacgcacgagaaggtgctggcgatcgtaaacgcgctggccgaaaacagggccatccggcc cgacgaggccggcctggtct acgacgcgctgcttcagcgcgtggctcgttacaacagcggcaacgtgcagaccaacctgg accggctggtgggggatgtg cgcgaggccgtggcgcagcgtgagcgcgcgcagcagcagggcaacctgggctccatggtt gcactaaacgccttcctgag tacacagcccgccaacgtgccgcggggacaggaggactacaccaactttgtgagcgcact gcggctaatggtgactgaga caccgcaaagtgaggtgtaccagtctgggccagactattttttccagaccagtagacaag gcctgcagaccgtaaacctg agccaggctttcaaaaacttgcaggggctgtggggggtgcgggctcccacaggcgaccgc gcgaccgtgtctagcttgct gacgcccaactcgcgcctgttgctgctgctaatagcgcccttcacggacagtggcagcgt gtcccgggacacatacctag gtcacttgctgacactgtaccgcgaggccataggtcaggcgcatgtggacgagcatactt tccaggagattacaagtgtc agccgcgcgctggggcaggaggacacgggcagcctggaggcaaccctaaactacctgctg accaaccggcggcagaagat cccctcgttgcacagtttaaacagcgaggaggagcgcattttgcgctacgtgcagcagag cgtgagccttaacctgatgc gcgacggggtaacgcccagcgtggcgctggacatgaccgcgcgcaacatggaaccgggca tgtatgcctcaaaccggccg tttatcaaccgcctaatggactacttgcatcgcgcggccgccgtgaaccccgagtatttc accaatgccatcttgaaccc gcactggctaccgccccctggtttctacaccgggggattcgaggtgcccgagggtaacga tggattcctctgggacgaca tagacgacagcgtgttttccccgcaaccgcagaccctgctagagttgcaacagcgcgagc aggcagaggcggcgctgcga aaggaaagcttccgcaggccaagcagcttgtccgatctaggcgctgcggccccgcggtca gatgctagtagcccatttcc aagcttgatagggtctcttaccagcactcgcaccacccgcccgcgcctgctgggcgagga ggagtacctaaacaactcgc tgctgcagccgcagcgcgaaaaaaacctgcctccggcatttcccaacaacgggatagaga gcctagtggacaagatgagt agatggaagacgtacgcgcaggagcacagggacgtgccaggcccgcgcccgcccacccgt cgtcaaaggcacgaccgtca gcggggtctggtgtgggaggacgatgactcggcagacgacagcagcgtcctggatttggg agggagtggcaacccgtttg cgcaccttcgccccaggctggggagaatgttttaaaaaaaaaaaagcatgatgcaaaata aaaaactcaccaaggccatg gcaccgagcgttggttttcttgtattccccttagtatgcggcgcgcggcgatgtatgagg aaggtcctcctccctcctac gagagtgtggtgagcgcggcgccagtggcggcggcgctgggttctcccttcgatgctccc ctggacccgccgtttgtgcc tccgcggtacctgcggcctaccggggggagaaacagcatccgttactctgagttggcacc cctattcgacaccacccgtg tgtacctggtggacaacaagtcaacggatgtggcatccctgaactaccagaacgaccaca gcaactttctgaccacggtc attcaaaacaatgactacagcccgggggaggcaagcacacagaccatcaatcttgacgac cggtcgcactggggcggcga cctgaaaaccatcctgcataccaacatgccaaatgtgaacgagttcatgtttaccaataa gtttaaggcgcgggtgatgg tgtcgcgcttgcctactaaggacaatcaggtggagctgaaatacgagtgggtggagttca cgctgcccgagggcaactac tccgagaccatgaccatagaccttatgaacaacgcgatcgtggagcactacttgaaagtg ggcagacagaacggggttct ggaaagcgacatcggggtaaagtttgacacccgcaacttcagactggggtttgaccccgt cactggtcttgtcatgcctg gggtatatacaaacgaagccttccatccagacatcattttgctgccaggatgcggggtgg acttcacccacagccgcctg agcaacttgttgggcatccgcaagcggcaacccttccaggagggctttaggatcacctac gatgatctggagggtggtaa cattcccgcactgttggatgtggacgcctaccaggcgagcttgaaagatgacaccgaaca gggcgggggtggcgcaggcg gcagcaacagcagtggcagcggcgcggaagagaactccaacgcggcagccgcggcaatgc agccggtggaggacatgaac gatcatgccattcgcggcgacacctttgccacacgggctgaggagaagcgcgctgaggcc gaagcagcggccgaagctgc cgcccccgctgcgcaacccgaggtcgagaagcctcagaagaaaccggtgatcaaacccct gacagaggacagcaagaaac gcagttacaacctaataagcaatgacagcaccttcacccagtaccgcagctggtaccttg catacaactacggcgaccct cagaccggaatccgctcatggaccctgctttgcactcctgacgtaacctgcggctcggag caggtctactggtcgttgcc agacatgatgcaagaccccgtgaccttccgctccacgcgccagatcagcaactttccggt ggtgggcgccgagctgttgc ccgtgcactccaagagcttctacaacgaccaggccgtctactcccaacteatccgccagt ttacctctctgacccacgtg ttcaatcgctttcccgagaaccagattttggcgcgcccgccagcccccaccatcaccacc gtcagtgaaaacgttcctgc tctcacagatcacgggacgctaccgctgcgcaacagcatcggaggagtccagcgagtgac cattactgacgccagacgcc gcacctgcccctacgtttacaaggccctgggcatagtctcgccgcgcgtcctatcgagcc gcactttttgagcaagcatg tccatccttatatcgcccagcaataacacaggctggggcctgcgcttcccaagcaagatg tttggcggggccaagaagcg ctccgaccaacacccagtgcgcgtgcgcgggcactaccgcgcgccctggggcgcgcacaa acgcggccgcactgggcgca ccaccgtcgatgacgccatcgacgcggtggtggaggaggcgcgcaactacacgcccacgc cgccaccagtgtccacagtg gacgcggccattcagaccgtggtgcgcggagcccggcgctatgctaaaatgaagagacgg cggaggcgcgtagcacgtcg ccaccgccgccgacccggcactgccgcccaacgcgcggcggcggccctgcttaaccgcgc acgtcgcaccggccgacggg cggccatgcgggccgctcgaaggctggccgcgggtattgtcactgtgccccccaggtcca ggcgacgagcggccgccgca gcagccgcggccattagtgctatgactcagggtcgcaggggcaacgtgtattgggtgcgc gactcggttagcggcctgcg cgtgcccgtgcgcacccgccccccgcgcaactagattgcaagaaaaaactacttagactc gtactgttgtatgtatccag cggcggcggcgcgcaacgaagctatgtccaagcgcaaaatcaaagaagagatgctccagg tcatcgcgccggagatctat ggccccccgaagaaggaagagcaggattacaagccccgaaagctaaagcgggtcaaaaag aaaaagaaagatgatgatga tgaacttgacgacgaggtggaactgctgcacgctaccgcgcccaggcgacgggtacagtg gaaaggtcgacgcgtaaaac gtgttttgcgacccggcaccaccgtagtctttacgcccggtgagcgctccacccgcacct acaagcgcgtgtatgatgag gtgtacggcgacgaggacctgcttgagcaggccaacgagcgcctcggggagtttgcctac ggaaagcggcataaggacat gctggcgttgccgctggacgagggcaacccaacacctagcctaaagcccgtaacactgca gcaggtgctgcccgcgcttg caccgtccgaagaaaagcgcggcctaaagcgcgagtctggtgacttggcacccaccgtgc agctgatggtacccaagcgc cagcgactggaagatgtcttggaaaaaatgaccgtggaacctgggctggagcccgaggtc cgcgtgcggccaatcaagca ggtggcgccgggactgggcgtgcagaccgtggacgttcagatacccactaccagtagcac cagtattgccaccgccacag agggcatggagacacaaacgtccccggttgcctcagcggtggcggatgccgcggtgcagg cggtcgctgcggccgcgtcc aagacctctacggaggtgcaaacggacccgtggatgtttcgcgtttcagccccccggcgc ccgcgcggttcgaggaagta cggcgccgccagcgcgctactgcccgaatatgccctacatccttccattgcgcctacccc cggctatcgtggctacacct accgccccagaagacgagcaactacccgacgccgaaccaccactggaacccgccgccgcc gtcgccgtcgccagcccgtg ctggccccgatttccgtgcgcagggtggctcgcgaaggaggcaggaccctggtgctgcca acagcgcgctaccaccccag catcgtttaaaagccggtctttgtggttcttgcagatatggccctcacctgccgcctccg tttcccggtgccgggattcc gaggaagaatgcaccgtaggaggggcatggccggccacggcctgacgggcggcatgcgtc gtgcgcaccaccggcggcgg cgcgcgtcgcaccgtcgcatgcgcggcggtatcctgcccctccttattccactgatcgcc gcggcgattggcgccgtgcc cggaattgcatccgtggccttgcaggcgcagagacactgattaaaaacaagttgcatgtg gaaaaatcaaaataaaaagt ctggactctcacgctcgcttggtcctgtaactattttgtagaatggaagacatcaacttt gcgtctctggccccgcgaca cggctcgcgcccgttcatgggaaactggcaagatatcggcaccagcaatatgagcggtgg cgccttcagctggggctcgc tgtggagcggcattaaaaatttcggttccaccgttaagaactatggcagcaaggcctgga acagcagcacaggccagatg ctgagggataagttgaaagagcaaaatttccaacaaaaggtggtagatggcctggcctct ggcattagcggggtggtgga cctggccaaccaggcagtgcaaaataagattaacagtaagcttgatccccgccctcccgt agaggagcctccaccggccg tggagacagtgtctccagaggggcgtggcgaaaagcgtccgcgccccgacagggaagaaa ctctggtgacgcaaatagac gagcctccctcgtacgaggaggcactaaagcaaggcctgcccaccacccgtcccatcgcg cccatggctaccggagtgct gggccagcacacacccgtaacgctggacctgcctccccccgccgacacccagcagaaacc tgtgctgccaggcccgaccg ccgttgttgtaacccgtcctagccgcgcgtccctgcgccgcgccgccagcggtccgcgat cgttgcggcccgtagccagt ggcaactggcaaagcacactgaacagcatcgtgggtctgggggtgcaatccctgaagcgc cgacgatgcttctgaatagc taacgtgtcgtatgtgtgtcatgtatgcgtccatgtcgccgccagaggagctgctgagcc gccgcgcgcccgctttccaa gatggctaccccttcgatgatgccgcagtggtcttacatgcacatctcgggccaggacgc ctcggagtacctgagccccg ggctggtgcagtttgcccgcgccaccgagacgtacttcagcctgaataacaagtttagaa accccacggtggcgcctacg cacgacgtgaccacagaccggtcccagcgtttgacgctgcggttcatccctgtggaccgt gaggatactgcgtactcgta caaggcgcggttcaccctagctgtgggtgataaccgtgtgctggacatggcttccacgta ctttgacatccgcggcgtgc tggacaggggccctacttttaagccctactctggcactgcctacaacgccctggctccca agggtgccccaaatccttgc gaatgggatgaagctgctactgctcttgaaataaacctagaagaagaggacgatgacaac gaagacgaagtagacgagca agctgagcagcaaaaaactcacgtatttgggcaggcgccttattctggtataaatattac aaaggagggtattcaaatag gtgtcgaaggtcaaacacctaaatatgccgataaaacatttcaacctgaacctcaaatag gagaatctcagtggtacgaa actgaaattaatcatgcagctgggagagtccttaaaaagactaccccaatgaaaccatgt tacggttcatatgcaaaacc cacaaatgaaaatggagggcaaggcattcttgtaaagcaacaaaatggaaagctagaaag tcaagtggaaatgcaatttt tctcaactactgaggcgaccgcaggcaatggtgataacttgactcctaaagtggtattgt acagtgaagatgtagatata gaaaccccagacactcatatttcttacatgcccactattaaggaaggtaactcacgagaa ctaatgggccaacaatctat gcccaacaggcctaattacattgcttttagggacaattttattggtctaatgtattacaa cagcacgggtaatatgggtg ttctggcgggccaagcatcgcagttgaatgctgttgtagatttgcaagacagaaacacag agctttcataccagcttttg cttgattccattggtgatagaaccaggtacttttctatgtggaatcaggctgttgacagc tatgatccagatgttagaat tattgaaaatcatggaactgaagatgaacttccaaattactgctttccactgggaggtgt gattaatacagagactctta ccaaggtaaaacctaaaacaggtcaggaaaatggatgggaaaaagatgctacagaatttt cagataaaaatgaaataaga gttggaaataattttgccatggaaatcaatctaaatgccaacctgtggagaaatttcctg tactccaacatagcgctgta tttgcccgacaagctaaagtacagtccttccaacgtaaaaatttctgataacccaaacac ctacgactacatgaacaagc gagtggtggctcccgggttagtggactgctacattaaccttggagcacgctggtcccttg actatatggacaacgtcaac ccatttaaccaccaccgcaatgctggcctgcgctaccgctcaatgttgctgggcaatggt cgctatgtgcccttccacat ccaggtgcctcagaagttctttgccattaaaaacctccttctcctgccgggctcatacac ctacgagtggaacttcagga aggatgttaacatggttctgcagagctccctaggaaatgacctaagggttgacggagcca gcattaagtttgatagcatt tgcctttacgccaccttcttccccatggcccacaacaccgcctccacgcttgaggccatg cttagaaacgacaccaacga ccagtcctttaacgactatctctccgccgccaacatgctctaccctatacccgccaacgc taccaacgtgcccatatcca tcccctcccgcaactgggcggctttccgcggctgggccttcacgcgccttaagactaagg aaaccccatcactgggctcg ggctacgacccttattacacctactctggctctataccctacctagatggaaccttttac ctcaaccacacctttaagaa ggtggccattacctttgactcttctgtcagctggcctggcaatgaccgcctgcttacccc caacgagtttgaaattaagc gctcagttgacggggagggttacaacgttgcccagtgtaacatgaccaaagactggttcc tggtacaaatgctagctaac tacaacattggctaccagggcttctatatcccagagagctacaaggaccgcatgtactcc ttctttagaaacttccagcc catgagccgtcaggtggtggatgatactaaatacaaggactaccaacaggtgggcatcct acaccaacacaacaactctg gatttgttggctaccttgcccccaccatgcgcgaaggacaggcctaccctgctaacttcc cctatccgcttataggcaag accgcagttgacagcattacccagaaaaagtttctttgcgatcgcaccctttggcgcatc ccattctccagtaactttat gtccatgggcgcactcacagacctgggccaaaaccttctctacgccaactccgcccacgc gctagacatgacttttgagg tggatcccatggacgagcccacccttctttatgttttgtttgaagtctttgacgtggtcc gtgtgcaccggccgcaccgc ggcgtcatcgaaaccgtgtacctgcgcacgcccttctcggccggcaacgccacaacataa agaagcaagcaacatcaaca acagctgccgccatgggctccagtgagcaggaactgaaagccattgtcaaagatcttggt tgtgggccatattttttggg cacctatgacaagcgctttccaggctttgtttctccacacaagctcgcctgcgccatagt caatacggccggtcgcgaga ctgggggcgtacactggatggcctttgcctggaacccgcactcaaaaacatgctacctct ttgagccctttggcttttct gaccagcgactcaagcaggtttaccagtttgagtacgagtcactcctgcgccgtagcgcc attgcttcttcccccgaccg ctgtataacgctggaaaagtccacccaaagcgtacaggggcccaactcggccgcctgtgg actattctgctgcatgtttc tccacgcctttgccaactggccccaaactcccatggatcacaaccccaccatgaacctta ttaccggggtacccaactcc atgctcaacagtccccaggtacagcccaccctgcgtcgcaaccaggaacagctctacagc ttcctggagcgccactcgcc ctacttccgcagccacagtgcgcagattaggagcgccacttctttttgtcacttgaaaaa catgtaaaaataatgtacta gagacactttcaataaaggcaaatgcttttatttgtacactctcgggtgattatttaccc ccacccttgccgtctgcgcc gtttaaaaatcaaaggggttctgccgcgcatcgctatgcgccactggcagggacacgttg cgatactggtgtttagtgct ccacttaaactcaggcacaaccatccgcggcagctcggtgaagttttcactccacaggct gcgcaccatcaccaacgcgt ttagcaggtcgggcgccgatatcttgaagtcgcagttggggcctccgccctgcgcgcgcg agttgcgatacacagggttg cagcactggaacactatcagcgccgggtggtgcacgctggccagcacgctcttgtcggag atcagatccgcgtccaggtc ctccgcgttgctcagggcgaacggagtcaactttggtagctgccttcccaaaaagggcgc gtgcccaggctttgagttgc actcgcaccgtagtggcatcaaaaggtgaccgtgcccggtctgggcgttaggatacagcg cctgcataaaagccttgatc tgcttaaaagccacctgagcctttgcgccttcagagaagaacatgccgcaagacttgccg gaaaactgattggccggaca ggccgcgtcgtgcacgcagcaccttgcgtcggtgttggagatctgcaccacatttcggcc ccaccggttcttcacgatct tggccttgctagactgctccttcagcgcgcgctgcccgttttcgctcgtcacatccattt caatcacgtgctccttattt atcataatgcttccgtgtagacacttaagctcgccttcgatctcagcgcagcggtgcagc cacaacgcgcagcccgtggg ctcgtgatgcttgtaggtcacctctgcaaacgactgcaggtacgcctgcaggaatcgccc catcatcgtcacaaaggtct tgttgctggtgaaggtcagctgcaacccgcggtgctcctcgttcagccaggtcttgcata cggccgccagagcttccact tggtcaggcagtagtttgaagttcgcctttagatcgttatccacgtggtacttgtccatc agcgcgcgcgcagcctccat gcccttctcccacgcagacacgatcggcacactcagcgggttcatcaccgtaatttcact ttccgcttcgctgggctctt cctcttcctcttgcgtccgcataccacgcgccactgggtcgtcttcattcagccgccgca ctgtgcgcttacctcctttg ccatgcttgattagcaccggtgggttgctgaaacccaccatttgtagcgccacatcttct ctttcttcctcgctgtccac gattacctctggtgatggcgggcgctcgggcttgggagaagggcgcttctttttcttctt gggcgcaatggccaaatccg ccgccgaggtcgatggccgcgggctgggtgtgcgcggcaccagcgcgtcttgtgatgagt cttcctcgtcctcggactcg atacgccgcctcatccgcttttttgggggcgcccggggaggcggcggcgacggggacggg gacgacacgtcctccatggt tgggggacgtcgcgccgcaccgcgtccgcgctcgggggtggtttcgcgctgctcctcttc ccgactggccatttccttct cctataggcagaaaaagatcatggagtcagtcgagaagaaggacagcctaaccgccccct ctgagttcgccaccaccgcc tccaccgatgccgccaacgcgcctaccaccttccccgtcgaggcacccccgcttgaggag gaggaagtgattatcgagca ggacccaggttttgtaagcgaagacgacgaggaccgctcagtaccaacagaggataaaaa gcaagaccaggacaacgcag aggcaaacgaggaacaagtcgggcggggggacgaaaggcatggcgactacctagatgtgg gagacgacgtgctgttgaag catctgcagcgccagtgcgccattatctgcgacgcgttgcaagagcgcagcgatgtgccc ctcgccatagcggatgtcag ccttgcctacgaacgccacctattctcaccgcgcgtaccccccaaacgccaagaaaacgg cacatgcgagcccaacccgc gcctcaacttctaccccgtatttgccgtgccagaggtgcttgccacctatcacatctttt tccaaaactgcaagataccc ctatcctgccgtgccaaccgcagccgagcggacaagcagctggccttgcggcagggcgct gtcatacctgatatcgcctc gctcaacgaagtgccaaaaatctttgagggtcttggacgcgacgagaagcgcgcggcaaa cgctctgcaacaggaaaaca gcgaaaatgaaagtcactctggagtgttggtggaactcgagggtgacaacgcgcgcctag ccgtactaaaacgcagcaTC GAGGTCACCCACTTTGCCTACCCGGCACTTAACCTACCCCCCAAGGTCTTGCCTACCACT CTGACATAATGGAAGACGTG AGCGGTGACGGTCTACTGgagtgtcactgtcgctgcaacctatgcaccccgcaccgctcc ctggtttgcaattcgcagct gcttaacgaaagtcaaattatcggtacctttgagctgcagggtccctcgcctgacgaaaa gtccgcggctccggggttga aactcactccggggctgtggacgtcggcttaccttcgcaaatttgtacctgaggactacc acgcccacgagattaggttc tacgaagaccaatcccgcccgccaaatgcggagcttaccgcctgcgtcattacccagggc cacattcttggccaattgca agccatcaacaaagcccgccaagagtttctgctacgaaagggacggggggtttacttgga cccccagtccggcgaggagc tcaacccaatccccccgccgccgcagccctatcagcagcagccgcgggcccttgcttccc aggatggcacccaaaaagaa gctgcagctgccgccgccacccacggacgaggaggaatactgggacagtcaggcagagga ggttttggacgaggaggagg aggacatgatggaagactgggagagcctagacgaggaagcttccgaggtcgaagaggtgt cagacgaaacaccgtcaccc tcggtcgcattcccctcgccggcgccccagaaatcggcaaccggttccagcatggctaca acctccgctcctcaggcgcc gccggcactgcccgttcgccgacccaaccgtagatgggacaccactggaaccagggccgg taagtccaagcagccgccgc cgttagcccaagagcaacaacagcgccaaggctaccgctcatggcgcgggcacaagaacg ccatagttgcttgcttgcaa gactgtgggggcaacatctccttcgcccgccgctttcttctctaccatcacggcgtggcc ttcccccgtaacatcctgca ttactaccgtcatctctacagcccatactgcaccggcggcagcggcagcggcagcaacag cagcggccacacagaagcaa aggcgaccggatagcaagactctgacaaagcccaagaaatccacagcggcggcagcagca ggaggaggagcgctgcgtct ggcgcccaacgaacccgtatcgacccgcgagcttagaaacaggatttttcccactctgta tgctatatttcaacagagca ggggccaagaacaagagctgaaaataaaaaacaggtctctgcgatccctcacccgcagct gcctgtatcacaaaagcgaa gatcagettcggcgcacgctggaagacgcggaggctctcttcagtaaatactgcgcgctg actcttaaggactagttteg cgccctttctcaaatttaagcgcgaaaactacgtcatctccagcggccacacccggcgcc agcacctgtcgtcagcgcca ttatgagcaaggaaattcccacgccctacatgtggagttaccagccacaaatgggacttg cggctggagctgcccaagac tactcaacccgaataaactacatgagcgcgggaccccacatgatatcccgggtcaacgga atccgcgcccaccgaaaccg aattctcttggaacaggcggctattaccaccacacctcgtaataaccttaatccccgtag ttggcccgctgccctggtgt accaggaaagtcccgctcccaccactgtggtacttcccagagacgcccaggccgaagttc agatgactaactcaggggcg cagcttgcgggcggctttcgtcacagggtgcggtcgcccgggcagggtataactcacctg acaatcagagggcgaggtat tcagctcaacgacgagtcggtgagctcctcgcttggtctccgtccggacgggacatttca gatcggcggcgccggccgtc cttcattcacgcctcgtcaggcaatcctaactctgcagacctcgtcctctgagccgcgct ctggaggcattggaactctg caatttattgaggagtttgtgccatcggtctactttaaccccttctcgggacctcccggc cactatccggatcaatttat tcctaactttgacgcggtaaaggactcggcggacggctacgactgaatgttaagtggaga ggcagagcaactgcgcctga aacacctggtccactgtcgccgccacaagtgctttgcccgcgactccggtgagttttgct actttgaattgcccgaggat catatcgagggcccggcgcacggcgtccggcttaccgcccagggagagcttgcccgtagc ctgattcgggagtttaccca gcgccccctgctagttgagcgggacaggggaccctgtgttctcactgtgatttgcaactg tcctaaccttggattacatc aagatctttgttgccatctctgtgctgagtataataaatacagaaattaaaatatactgg ggctcctatcgccatcctgt aaacgccaccgtcttcacccgcccaagcaaaccaaggcgaaccttacctggtacttttaa catctctccctctgtgattt acaacagtttcaacccagacggagtgagtctacgagagaacctctccgagctcagetact ccatcagaaaaaacaccacc ctccttacctgccgggaacgtacgagtgcgtcaccggccgctgcaccacacctaccgcct gaccgtaaaccagacttttt ccggacagacctcaataactctgtttaccagaacaggaggtgagcttagaaaacccttag ggtattaggccaaaggcgca gctactgtggggtttatgaacaattcaagcaactctacgggctattctaattcaggtttc tctagaatcggggttggggt tattctctgtcttgtgattctctttattcttatactaacgcttctctgcctaaggctcgc cgcctgctgtgtgcacattt gcatttattgtcagctttttaaacgctggggtcgccacccaagatgattaggtacataat cctaggtttactcacccttg cgtcagcccacggtaccacccaaaaggtggattttaaggagccagcctgtaatgttacat tcgcagctgaagctaatgag tgcaccactcttataaaatgcaccacagaacatgaaaagctgcttattcgccacaaaaac aaaattggcaagtatgctgt ttatgctatttggcagccaggtgacactacagagtataatgttacagttttccagggtaa aagtcataaaacttttatgt atacttttccattttatgaaatgtgcgacattaccatgtacatgagcaaacagtataagt tgtggcccccacaaaattgt gtggaaaacactggcactttctgctgcactgctatgctaattacagtgctcgctttggtc tgtaccctactctatattaa atacaaaagcagacgcagctttattgaggaaaagaaaatgccttaatttactaagttaca aagctaatgtcaccactaac tgctttactcgctgcttgcaaaacaaattcaaaaagttagcattataattagaataggat ttaaaccccccggtcatttc ctgctcaataccattcccctgaacaattgactctatgtgggatatgctccagcgctacaa ccttgaagtcaggcttcctg gatgtcagcatctgactttggccagcacctgtcccgcggatttgttccagtccaactaca gcgacccaccctaacagaga tgaccaacacaaccaacgcggccgccgctaccggacttacatctaccacaaatacacccc aagtttctgcctttgtcaat aactgggataacttgggcatgtggtggttctccatagcgcttatgtttgtatgccttatt attatgtggctcatctgctg cctaaagcgcaaacgcgcccgaccacccatctatagtcccatcattgtgctacacccaaa caatgatggaatccatagat tggacggactgaaacacatgttcttttctcttacagtatgattaaatgagacatgattcc tcgagtttttatattactga cccttgttgcgcttttttgtgcgtgctccacattggctgcggtttctcacatcgaagtag actgcattccagccttcaca gtctatttgctttacggatttgtcaccctcacgctcatctgcagcctcatcactgtggtc atcgcctttatccagtgcat tgactgggtctgtgtgcgctttgcatatctcagacaccatccccagtacagggacaggac tatagctgagcttcttagaa ttctttaattatgaaatttactgtgacttttctgctgattatttgcaccctatctgcgtt ttgttccccgacctccaagc ctcaaagacatatatcatgcagattcactcgtatatggaatattccaagttgctacaatg aaaaaagcgatctttccgaa gcctggttatatgcaatcatctctgttatggtgttctgcagtaccatcttagccctagct atatatccctaccttgacat tggctggaaacgaatagatgccatgaaccacccaactttccccgcgcccgctatgcttcc actgcaacaagttgttgccg gcggctttgtcccagccaatcagcctcgccccacttctcccacccccactgaaatcagct actttaatctaacaggagga gatgactgacaccctagatctagaaatggacggaattattacagagcagcgcctgctaga aagacgcagggcagcggccg agcaacagcgcatgaatcaagagctccaagacatggttaacttgcaccagtgcaaaaggg gtatcttttgtctggtaaag caggccaaagtcacctacgacagtaataccaccggacaccgccttagctacaagttgcca accaagcgtcagaaattggt ggtcatggtgggagaaaagcccattaccataactcagcactcggtagaaaccgaaggctg cattcactcaccttgtcaag gacctgaggatctctgcacccttattaagaccctgtgcggtctcaaagatcttattccct ttaactaataaaaaaaaata ataaagcatcacttacttaaaatcagttagcaaatttctgtccagtttattcagcagcac ctccttgccctcctcccagc tctggtattgcagcttcctcctggctgcaaactttctccacaatctaaatggaatgtcag tttcctcctgttcctgtcca tccgcacccactatcttcatgttgttgcagatgaagcgcgcaagaccgtctgaagatacc ttcaaccccgtgtatccata tgacacggaaaccggtcctccaactgtgccttttcttactcctccctttgtatcccccaa tgggtttcaagagagtcccc ctggggtactctctttgcgcctatccgaacctctagttacctccaatggcatgcttgcgc tcaaaatgggcaacggcctc tctctggacgaggccggcaaccttacctcccaaaatgtaaccactgtgagcccacctctc aaaaaaaccaagtcaaacat aaacctggaaatatctgcacccctcacagttacctcagaagccctaactgtggctgccgc cgcacctctaatggtcgcgg gcaacacactcaccatgcaatcacaggccccgctaaccgtgcacgactccaaacttagca ttgccacccaaggacccctc acagtgtcagaaggaaagctagccctgcaaacatcaggccccctcaccaccaccgatagc agtacccttactatcactgc ctcaccccctctaactactgccactggtagcttgggcattgacttgaaagagcccattta tacacaaaatggaaaactag gactaaagtacggggctcctttgcatgtaacagacgacctaaacactttgaccgtagcaa ctggtccaggtgtgactatt aataatacttccttgcaaactaaagttactggagccttgggttttgattcacaaggcaat atgcaacttaatgtagcagg aggactaaggattgattctcaaaacagacgccttatacttgatgttagttatccgtttga tgctcaaaaccaactaaatc taagactaggacagggccctctttttataaactcagcccacaacttggatattaactaca acaaaggcctttacttgttt acagcttcaaacaattccaaaaagcttgaggttaacctaagcactgccaaggggttgatg tttgacgctacagccatagc cattaatgcaggagatgggcttgaatttggttcacctaatgcaccaaacacaaatcccct caaaacaaaaattggccatg gcctagaatttgattcaaacaaggctatggttcctaaactaggaactggccttagttttg acagcacaggtgccattaca gtaggaaacaaaaataatgataagctaactttgtggaccacaccagctccatctcctaac tgtagactaaatgcagagaa agatgctaaactcactttggtcttaacaaaatgtggcagtcaaatacttgctacagtttc agttttggctgttaaaggca gtttggctccaatatctggaacagttcaaagtgctcatcttattataagatttgacgaaa atggagtgctactaaacaat tccttcctggacccagaatattggaactttagaaatggagatcttactgaaggcacagcc tatacaaacgctgttggatt tatgcctaacctatcagcttatccaaaatctcacggtaaaactgccaaaagtaacattgt cagtcaagtttacttaaacg gagacaaaactaaacctgtaacactaaccattacactaaacggtacacaggaaacaggag acacaactccaagtgcatac tctatgtcattttcatgggactggtctggccacaactacattaatgaaatatttgccaca tcctcttacactttttcata cattgcccaagaataaagaatcgtttgtgttatgtttcaacgtgtttatttttcaattgc agaaaatttcaagtcatttt tcattcagtagtatagccccaccaccacatagcttatacagatcaccgtaccttaatcaa actcacagaaccctagtatt caacctgccacctccctcccaacacacagagtacacagtcctttctccccggctggcctt aaaaagcatcatatcatggg taacagacatattcttaggtgttatattccacacggtttcctgtcgagccaaacgcteat cagtgatattaataaactec ccgggcagctcacttaagttcatgtcgctgtccagctgctgagccacaggctgctgtcca acttgcggttgcttaacggg cggcgaaggagaagtccacgcctacatgggggtagagtcataatcgtgcatcaggatagg gcggtggtgctgcagcagcg cgcgaataaactgctgccgccgccgctccgtcctgcaggaatacaacatggcagtggtct cctcagcgatgattcgcacc gcccgcagcataaggcgccttgtcctccgggcacagcagcgcaccctgatctcacttaaa tcagcacagtaactgcagca cagcaccacaatattgttcaaaatcccacagtgcaaggcgctgtatccaaagctcatggc ggggaccacagaacccacgt ggccatcataccacaagcgcaggtagattaagtggcgacccctcataaacacgctggaca taaacattacctcttttggc atgttgtaattcaccacctcccggtaccatataaacctctgattaaacatggcgccatcc accaccatcctaaaccagct ggccaaaacctgcccgccggctatacactgcagggaaccgggactggaacaatgacagtg gagagcccaggactcgtaac catggatcatcatgctcgtcatgatatcaatgttggcacaacacaggcacacgtgcatac acttcctcaggattacaagc tcctcccgcgttagaaccatatcccagggaacaacccattcctgaatcagcgtaaatccc acactgcagggaagacctcg cacgtaactcacgttgtgcattgtcaaagtgttacattcgggcagcagcggatgatcctc cagtatggtagcgcgggttt ctgtctcaaaaggaggtagacgatccctactgtacggagtgcgccgagacaaccgagatc gtgttggtcgtagtgtcatg ccaaatggaacgccggacgtagtcatatttcctgaagcaaaaccaggtgcgggcgtgaca aacagatctgcgtctccggt ctcgccgcttagatcgctctgtgtagtagttgtagtatatccactctctcaaagcatcca ggcgccccctggcttcgggt tctatgtaaactccttcatgcgccgctgccctgataacatccaccaccgcagaataagcc acacccagccaacctacaca ttcgttctgcgagtcacacacgggaggagcgggaagagctggaagaaccatgtttttttt tttattccaaaagattatcc aaaacctcaaaatgaagatctattaagtgaacgcgctcccctccggtggcgtggtcaaac tctacagccaaagaacagat aatggcatttgtaagatgttgcacaatggcttccaaaaggcaaacggccctcacgtccaa gtggacgtaaaggctaaacc cttcagggtgaatctcctctataaacattccagcaccttcaaccatgcccaaataattct catctcgccaccttctcaat atatctctaagcaaatcccgaatattaagtccggccattgtaaaaatctgctccagagcg ccctccaccttcagcctcaa gcagcgaatcatgattgcaaaaattcaggttcctcacagacctgtataagattcaaaagc ggaacattaacaaaaatacc gcgatcccgtaggtcccttcgcagggccagctgaacataatcgtgcaggtctgcacggac cagcgcggccacttccccgc caggaaccttgacaaaagaacccacactgattatgacacgcatactcggagctatgctaa ccagcgtagccccgatgtaa gctttgttgcatgggcggcgatataaaatgcaaggtgctgctcaaaaaatcaggcaaagc ctcgcgcaaaaaagaaagca catcgtagtcatgctcatgcagataaaggcaggtaagctccggaaccaccacagaaaaag acaccatttttctctcaaac atgtctgcgggtttctgcataaacacaaaataaaataacaaaaaaacatttaaacattag aagcctgtcttacaacagga aaaacaacccttataagcataagacggactacggccatgccggcgtgaccgtaaaaaaac tggtcaccgtgattaaaaag caccaccgacagctcctcggtcatgtccggagtcataatgtaagactcggtaaacacatc aggttgattcatcggtcagt gctaaaaagcgaccgaaatagcccgggggaatacatacccgcaggcgtagagacaacatt acagcccccataggaggtat aacaaaattaataggagagaaaaacacataaacacctgaaaaaccctcctgcctaggcaa aatagcaccctcccgctcca gaacaacatacagcgcttcacagcggcagcctaacagtcagccttaccagtaaaaaagaa aacctattaaaaaaacacca ctcgacacggcaccagctcaatcagtcacagtgtaaaaaagggccaagtgcagagcgagt atatataggactaaaaaatg acgtaacggttaaagtccacaaaaaacacccagaaaaccgcacgcgaacctacgcccaga aacgaaagccaaaaaaccca caacttcctcaaatcgtcacttccgttttcccacgttacgtaacttcccattttaagaaa actacaattcccaacacata caagttactccgccctaaaacctacgtcacccgccccgttcccacgccccgcgccacgtc acaaactccacccccteatt atcatattggcttcaatccaaaataaggtatattattgatgatgatttaaatgccgcagt actgttgtaattcattaagc attctgccgacatggaagccatcacaaacggcatgatgaacctgaatcgccagcggcatc agcaccttgtcgccttgcgt ataatatttgcccatggtgaaaacgggggcgaagaagttgtccatattggccacgtttaa atcaaaactggtgaaactca cccagggattggctgagacgaaaaacatattctcaataaaccctttagggaaataggcca ggttttcaccgtaacacgcc acatcttgcgaatatatgtgtagaaactgccggaaatcgtcgtggtattcactccagagc gatgaaaacgtttcagtttg ctcatggaaaacggtgtaacaagggtgaacactatcccatatcaccagctcaccgtcttt cattgccatacggaattccg gatgagcattcatcaggcgggcaagaatgtgaataaaggccggataaaacttgtgcttat ttttctttacggtctttaaa aaggccgtaatatccagctgaacggtctggttataggtacattgagcaactgactgaaat gcctcaaaatgttctttacg atgccattgggatatatcaacggtggtatatccagtgatttttttctccattttagcttc cttagctcctgaaaatctcg ataactcaaaaaatacgcccggtagtgatcttatttcattatggtgaaagttggaacctc ttacgtgccgatcaacgtct cattttcgccaaaagttggcccagggcttcccggtatcaacagggacaccaggatttatt tattctgcgaagtgatcttc cgtcacaggtatttattcgcgataagctcatggagcggcgtaaccgtcgcacaggaagga cagagaaagcgcggatctgg gaagtgacggacagaacggtcaggacctggattggggaggcggttgccgccgctgctgct gacggtgtgacgttctctgt tccggtcacaccacatacgttccgccattcctatgcgatgcacatgctgtatgccggtat accgctgaaagttctgcaaa gcctgatgggacataagtccatcagttcaacggaagtctacacgaaggtttttgcgctgg atgtggctgcccggcaccgg gtgcagtttgcgatgccggagtctgatgcggttgcgatgctgaaacaattatcctgagaa taaatgccttggcctttata tggaaatgtggaactgagtggatatgctgtttttgtctgttaaacagagaagctggctgt tatccactgagaagcgaacg aaacagtcgggaaaatctcccattatcgtagagatccgcattattaatctcaggagcctg tgtagcgtttataggaagta gtgttctgtcatgatgcctgcaagcggtaacgaaaacgatttgaatatgccttcaggaac aatagaaatcttcgtgcggt gttacgttgaagtggagcggattatgtcagcaatggacagaacaacctaatgaacacaga accatgatgtggtctgtcct tttacagccagtagtgctcgccgcagtcgagcgacagggcgaagccctcgagtgagcgag gaagcaccagggaacagcac ttatatattctgcttacacacgatgcctgaaaaaacttcccttggggttatccacttatc cacggggatatttttataat tattttttttatagtttttagatcttcttttttagagcgccttgtaggcctttatccatg ctggttctagagaaggtgtt gtgacaaattgccctttcagtgtgacaaatcaccctcaaatgacagtcctgtctgtgaca aattgcccttaaccctgtga caaattgccctcagaagaagctgttttttcacaaagttatccctgcttattgactctttt ttatttagtgtgacaatcta aaaacttgtcacacttcacatggatctgtcatggcggaaacagcggttatcaatcacaag aaacgtaaaaatagcccgcg aatcgtccagtcaaacgacctcactgaggcggcatatagtctctcccgggatcaaaaacg tatgctgtatctgttcgttg accagatcagaaaatctgatggcaccctacaggaacatgacggtatctgcgagatccatg ttgctaaatatgctgaaata ttcggattgacctctgcggaagccagtaaggatatacggcaggcattgaagagtttcgcg gggaaggaagtggtttttta tcgccctgaagaggatgccggcgatgaaaaaggctatgaatcttttccttggtttatcaa acgtgcgcacagtccatcca gagggctttacagtgtacatatcaacccatatcteattcccttctttatcgggttacaga accggtttacgcagtttegg cttagtgaaacaaaagaaatcaccaatccgtatgccatgcgtttatacgaatccctgtgt cagtatcgtaagccggatgg ctcaggcatcgtctctctgaaaatcgactggatcatagagcgttaccagctgcctcaaag ttaccagcgtatgcctgact tccgccgccgcttcctgcaggtctgtgttaatgagatcaacagcagaactccaatgcgcc tctcatacattgagaaaaag aaaggccgccagacgactcatatcgtattttccttccgcgatatcacttccatgacgaca ggatagtctgagggttatct gtcacagatttgagggtggttcgtcacatttgttctgacctactgagggtaatttgtcac agttttgctgtttccttcag cctgcatggattttctcatactttttgaactgtaatttttaaggaagccaaatttgaggg cagtttgtcacagttgattt ccttctctttcccttcgtcatgtgacctgatatcgggggttagttcgtcatcattgatga gggttgattatcacagttta ttactctgaattggctatccgcgtgtgtacctctacctggagtttttcccacggtggata tttcttcttgcgctgagcgt aagagctatctgacagaacagttcttctttgcttcctcgccagttcgctcgctatgctcg gttacacggctgcggcgagc gctagtgataataagtgactgaggtatgtgctcttcttatctccttttgtagtgttgctc ttattttaaacaactttgcg gttttttgatgactttgcgattttgttgttgctttgcagtaaattgcaagatttaataaa aaaacgcaaagcaatgatta aaggatgttcagaatgaaactcatggaaacacttaaccagtgcataaacgctggtcatga aatgacgaaggctatcgcca ttgcacagtttaatgatgacagcccggaagcgaggaaaataacccggcgctggagaatag gtgaagcagcggatttagtt ggggtttcttctcaggctatcagagatgccgagaaagcagggcgactaccgcacccggat atggaaattcgaggacgggt tgagcaacgtgttggttatacaattgaacaaattaatcatatgcgtgatgtgtttggtac gcgattgcgacgtgctgaag acgtatttccaccggtgatcggggttgctgcccataaaggtggcgtttacaaaacctcag tttctgttcatcttgctcag gatctggctctgaaggggctacgtgttttgctcgtggaaggtaacgacccccagggaaca gcctcaatgtatcacggatg ggtaccagatcttcatattcatgcagaagacactctcctgcctttctatcttggggaaaa ggacgatgtcacttatgcaa taaagcccacttgctggccggggcttgacattattccttcctgtctggctctgcaccgta ttgaaactgagttaatgggc aaatttgatgaaggtaaactgcccaccgatccacacctgatgctccgactggccattgaa actgttgctcatgactatga tgtcatagttattgacagcgcgcctaacctgggtatcggcacgattaatgtcgtatgtgc tgctgatgtgctgattgttc ccacgcctgctgagttgtttgactacacctccgcactgcagtttttcgatatgcttcgtg atctgctcaagaacgttgat cttaaagggttcgagcctgatgtacgtattttgcttaccaaatacagcaatagtaatggc tctcagtccccgtggatgga ggagcaaattcgggatgcctggggaagcatggttctaaaaaatgttgtacgtgaaacgga tgaagttggtaaaggtcaga tccggatgagaactgtttttgaacaggccattgatcaacgctcttcaactggtgcctgga gaaatgctctttctatttgg gaacctgtctgcaatgaaattttcgatcgtctgattaaaccacgctgggagattagataa tgaagcgtgcgcctgttatt ccaaaacatacgctcaatactcaaccggttgaagatacttcgttatcgacaccagctgcc ccgatggtggattcgttaat tgcgcgcgtaggagtaatggctcgcggtaatgccattactttgcctgtatgtggtcggga tgtgaagtttactcttgaag tgctccggggtgatagtgttgagaagacctctcgggtatggtcaggtaatgaacgtgacc aggagctgcttactgaggac gcactggatgatcteatcccttcttttctactgactggtcaacagacaccggcgttcggt cgaagagtatctggtgtcat agaaattgccgatgggagtcgccgtcgtaaagctgctgcacttaccgaaagtgattatcg tgttctggttggcgagctgg atgatgagcagatggctgcattatccagattgggtaacgattatcgcccaacaagtgctt atgaacgtggtcagcgttat gcaagccgattgcagaatgaatttgctggaaatatttctgcgctggctgatgcggaaaat atttcacgtaagattattac ccgctgtatcaacaccgccaaattgcctaaatcagttgttgctcttttttctcaccccgg tgaactatctgcccggtcag gtgatgcacttcaaaaagcctttacagataaagaggaattacttaagcagcaggcatcta accttcatgagcagaaaaaa gctggggtgatatttgaagctgaagaagttatcactcttttaacttctgtgcttaaaacg tcatctgcatcaagaactag tttaagctcacgacatcagtttgctcctggagcgacagtattgtataagggcgataaaat ggtgcttaacctggacaggt ctcgtgttccaactgagtgtatagagaaaattgaggccattcttaaggaacttgaaaagc cagcaccctgatgcgaccac gttttagtctacgtttatctgtctttacttaatgtcctttgttacaggccagaaagcata actggcctgaatattctetc tgggcccactgttccacttgtatcgtcggtctgataatcagactgggaccacggtcccac tcgtatcgtcggtctgatta ttagtctgggaccacggtcccactcgtatcgtcggtctgattattagtctgggaccacgg tcccactcgtatcgtcggtc tgataatcagactgggaccacggtcccactcgtatcgtcggtctgattattagtctggga ccatggtcccactcgtatcg tcggtctgattattagtctgggaccacggtcccactcgtatcgtcggtctgattattagt ctggaaccacggtcccactc gtatcgtcggtctgattattagtctgggaccacggtcccactcgtatcgtcggtctgatt attagtctgggaccacgatc ccactcgtgttgtcggtctgattatcggtctgggaccacggtcccacttgtattgtcgat cagactatcagcgtgagact acgattccatcaatgcctgtcaagggcaagtattgacatgtcgtcgtaacctgtagaacg gagtaacctcggtgtgcggt tgtatgcctgctgtggattgctgctgtgtcctgcttatccacaacattttgcgcacggtt atgtggacaaaatacctgtt accatttccatttaaatcatcatcaataatataccttattttggattgaagccaatatga taatgagggggtggagtttg tgacgtggcgcggggcgtgggaacggggcgggtgacgtagtagtgtggcggaagtgtgat gttgcaagtgtggcggaaca catgtaagcgacggatgtggcaaaagtgacgtttttggtgtgcgccggtgtacacaggaa gtgacaattttcgcgcggtt ttaggcggatgttgtagtaaatttgggcgtaaccgagtaagatttggccattttcgcggg aaaactgaataagaggaagt gaaatctgaataattttgtgttactcatagcgcgtaatatttgtctagggccgcggggac tttgaccgtttacgtggaga ctcgcccaggtgtttttctcaggtgttttccgcgttccgggtcaaagttggcgtttt

SEQ ID NO: 46 (Human Adenovirus 5 complete genome, 35938 nucleotides)

1 catcatcaat aatatacctt attttggatt gaagecaata tgataatgag ggggtggagt

61 ttgtgacgtg gcgcggggcg tgggaacggg gcgggtgacg tagtagtgtg gcggaagtgt

121 gatgttgcaa gtgtggcgga acacatgtaa gcgacggatg tggcaaaagt gacgtttttg

181 gtgtgcgccg gtgtacacag gaagtgacaa ttttcgcgcg gttttaggcg gatgttgtag

241 taaatttggg cgtaaccgag taagatttgg ccattttcgc gggaaaactg aataagagga

301 agtgaaatct gaataatttt gtgttactca tagegegtaa tatttgtcta gggccgcggg

361 gactttgacc gtttacgtgg agactcgccc aggtgttttt ctcaggtgtt ttccgcgttc

421 egggtcaaag ttggcgtttt attattatag tcagctgacg tgtagtgtat ttataccegg

481 tgagttcctc aagaggecac tcttgagtgc cagegagtag agttttctcc tccgagccgc

541 tccgacaccg ggactgaaaa tgagacatat tatctgccac ggaggtgtta ttaccgaaga

601 aatggccgcc agtcttttgg accagctgat cgaagaggta ctggctgata atcttccacc

661 tcctagccat tttgaaccac ctacccttca cgaactgtat gatttagacg tgacggcccc

721 cgaagatccc aacgaggagg eggtttcgea gatttttccc gactctgtaa tgttggcggt

781 gcaggaaggg attgacttac tcacttttcc gccggcgccc ggttctccgg agccgcctca

841 cctttcccgg cagcccgagc ageeggagea gagagecttg ggtccggttt etatgecaaa

901 ccttgtaccg gaggtgatcg atcttacctg ccacgaggct ggctttccac ccagtgacga

961 cgaggatgaa gagggtgagg agtttgtgtt agattatgtg gagcaccccg ggcacggttg

1021 caggtcttgt cattatcacc ggaggaatac gggggaccca gatattatgt gttcgctttg

1081 ctatatgagg acctgtggca tgtttgtcta cagtaagtga aaattatggg cagtgggtga

1141 tagagtggtg ggtttggtgt ggtaattttt tttttaattt ttacagtttt gtggtttaaa

1201 gaattttgta ttgtgatttt tttaaaaggt cctgtgtctg aacctgagcc tgageccgag

1261 ccagaaccgg agectgeaag acctacccgc cgtcctaaaa tggcgcctgc tatcctgaga 1321 cgcccgacat cacctgtgtc tagagaatgc aatagtagta cggatagctg tgactccggt

1381 ccttctaaca cacctcctga gatacacccg gtggtcccgc tgtgccccat taaaccagtt

1441 gccgtgagag ttggtgggcg tcgccaggct gtggaatgta tcgaggactt gcttaacgag

1501 cctgggcaac ctttggactt gagctgtaaa cgccccaggc cataaggtgt aaacctgtga 1561 ttgcgtgtgt ggttaacgcc tttgtttgct gaatgagttg atgtaagttt aataaagggt

1621 gagataatgt ttaacttgca tggcgtgtta aatggggcgg ggcttaaagg gtatataatg

1681 cgccgtgggc taatcttggt tacatctgac ctcatggagg cttgggagtg tttggaagat

1741 ttttctgctg tgcgtaactt gctggaacag agctctaaca gtacctcttg gttttggagg

1801 tttctgtggg gctcatccca ggcaaagtta gtctgcagaa ttaaggagga ttacaagtgg 1861 gaatttgaag agcttttgaa atcctgtggt gagctgtttg attctttgaa tctgggtcac

1921 caggcgcttt tccaagagaa ggtcatcaag actttggatt tttccacacc ggggcgcgct

1981 gcggctgctg ttgctttttt gagttttata aaggataaat ggagcgaaga aacccatctg

2041 agcggggggt acctgctgga ttttctggcc atgcatctgt ggagagcggt tgtgagacac

2101 aagaatcgcc tgctactgtt gtcttccgtc cgcccggcga taataccgac ggaggagcag 2161 cagcagcagc aggaggaagc caggcggcgg cggcaggagc agagcccatg gaacccgaga

2221 gccggcctgg accctcggga atgaatgttg tacaggtggc tgaactgtat ccagaactga

2281 gacgcatttt gacaattaca gaggatgggc aggggctaaa gggggtaaag agggagcggg

2341 gggcttgtga ggctacagag gaggctagga atctagcttt tagcttaatg accagacacc

2401 gtcctgagtg tattactttt caacagatca aggataattg cgctaatgag cttgatctgc 2461 tggcgcagaa gtattccata gagcagctga ccacttactg gctgcagcca ggggatgatt

2521 ttgaggaggc tattagggta tatgcaaagg tggcacttag gccagattgc aagtacaaga

2581 tcagcaaact tgtaaatatc aggaattgtt gctacatttc tgggaacggg gccgaggtgg

2641 agatagatac ggaggatagg gtggccttta gatgtagcat gataaatatg tggccggggg

2701 tgcttggcat ggacggggtg gttattatga atgtaaggtt tactggcccc aattttagcg 2761 gtacggtttt cctggccaat accaacctta tcctacacgg tgtaagcttc tatgggttta

2821 acaatacctg tgtggaagcc tggaccgatg taagggttcg gggctgtgcc ttttactgct

2881 gctggaaggg ggtggtgtgt cgccccaaaa gcagggcttc aattaagaaa tgcctctttg

2941 aaaggtgtac cttgggtatc ctgtctgagg gtaactccag ggtgcgccac aatgtggcct

3001 ccgactgtgg ttgcttcatg ctagtgaaaa gcgtggctgt gattaagcat aacatggtat 3061 gtggcaactg cgaggacagg gcctctcaga tgctgacctg ctcggacggc aactgtcacc

3121 tgctgaagac cattcacgta gccagccact ctcgcaaggc ctggccagtg tttgagcata

3181 acatactgac ccgctgttcc ttgcatttgg gtaacaggag gggggtgttc ctaccttacc

3241 aatgcaattt gagtcacact aagatattgc ttgagcccga gagcatgtcc aaggtgaacc

3301 tgaacggggt gtttgacatg accatgaaga tctggaaggt gctgaggtac gatgagaccc 3361 gcaccaggtg cagaccctgc gagtgtggcg gtaaacatat taggaaccag cctgtgatgc

3421 tggatgtgac cgaggagctg aggcccgatc acttggtgct ggcctgcacc cgcgctgagt

3481 ttggctctag cgatgaagat acagattgag gtactgaaat gtgtgggcgt ggcttaaggg

3541 tgggaaagaa tatataaggt gggggtctta tgtagttttg tatctgtttt gcagcagccg

3601 ccgccgccat gagcaccaac tcgtttgatg gaagcattgt gagctcatat ttgacaacgc 3661 gcatgccccc atgggccggg gtgcgtcaga atgtgatggg ctccagcatt gatggtcgcc

3721 ccgtcctgcc cgcaaactct actaccttga cctacgagac cgtgtctgga acgccgttgg

3781 agactgcagc ctccgccgcc gcttcagccg ctgcagccac cgcccgcggg attgtgactg 3841 actttgcttt cctgagcccg cttgcaagca gtgcagcttc ccgttcatcc gcccgcgatg

3901 acaagttgac ggctcttttg gcacaattgg attctttgac ccgggaactt aatgtcgttt

3961 ctcagcagct gttggatctg cgccagcagg tttctgccct gaaggcttcc tcccctccca

4021 atgcggttta aaacataaat aaaaaaccag actctgtttg gatttggatc aagcaagtgt 4081 cttgctgtct ttatttaggg gttttgcgcg cgcggtaggc ccgggaccag cggtctcggt

4141 cgttgagggt cctgtgtatt ttttccagga cgtggtaaag gtgactctgg atgttcagat

4201 acatgggcat aagcccgtct ctggggtgga ggtagcacca ctgcagagct tcatgctgcg

4261 gggtggtgtt gtagatgatc cagtcgtagc aggagcgctg ggcgtggtgc ctaaaaatgt

4321 ctttcagtag caagctgatt gccaggggca ggcccttggt gtaagtgttt acaaagcggt 4381 taagctggga tgggtgcata cgtggggata tgagatgcat cttggactgt atttttaggt

4441 tggctatgtt cccagccata tccctccggg gattcatgtt gtgcagaacc accagcacag

4501 tgtatccggt gcacttggga aatttgtcat gtagcttaga aggaaatgcg tggaagaact

4561 tggagacgcc cttgtgacct ccaagatttt ccatgcattc gtccataatg atggcaatgg

4621 gcccacgggc ggcggcctgg gcgaagatat ttctgggatc actaacgtca tagttgtgtt 4681 ccaggatgag atcgtcatag gccattttta caaagcgcgg gcggagggtg ccagactgcg

4741 gtataatggt tccatccggc ccaggggcgt agttaccctc acagatttgc atttcccacg

4801 ctttgagttc agatgggggg atcatgtcta cctgcggggc gatgaagaaa acggtttccg

4861 gggtagggga gatcagctgg gaagaaagca ggttcctgag cagctgcgac ttaccgcagc

4921 cggtgggccc gtaaatcaca cctattaccg ggtgcaactg gtagttaaga gagctgcagc 4981 tgccgtcatc cctgagcagg ggggccactt cgttaagcat gtccctgact cgcatgtttt

5041 ccctgaccaa atccgccaga aggcgctcgc cgcccagcga tagcagttct tgcaaggaag

5101 caaagttttt caacggtttg agaccgtccg ccgtaggcat gcttttgagc gtttgaccaa

5161 gcagttccag gcggtcccac agctcggtca cctgctctac ggcatctcga tccagcatat

5221 ctcctcgttt cgcgggttgg ggcggctttc gctgtacggc agtagtcggt gctcgtccag 5281 acgggccagg gtcatgtctt tccacgggcg cagggtcctc gtcagcgtag tctgggtcac

5341 ggtgaagggg tgcgctccgg gctgcgcgct ggccagggtg cgcttgaggc tggtcctgct

5401 ggtgctgaag cgctgccggt cttcgccctg cgcgtcggcc aggtagcatt tgaccatggt

5461 gtcatagtcc agcccctccg cggcgtggcc cttggcgcgc agcttgccct tggaggaggc

5521 gccgcacgag gggcagtgca gacttttgag ggcgtagagc ttgggcgcga gaaataccga 5581 ttccggggag taggcatccg cgccgcaggc cccgcagacg gtctcgcatt ccacgagcca

5641 ggtgagctct ggccgttcgg ggtcaaaaac caggtttccc ccatgctttt tgatgcgttt

5701 cttacctctg gtttccatga gccggtgtcc acgctcggtg acgaaaaggc tgtccgtgtc

5761 cccgtataca gacttgagag gcctgtcctc gagcggtgtt ccgcggtcct cctcgtatag

5821 aaactcggac cactctgaga caaaggctcg cgtccaggcc agcacgaagg aggctaagtg 5881 ggaggggtag cggtcgttgt ccactagggg gtccactcgc tccagggtgt gaagacacat

5941 gtcgccctct tcggcatcaa ggaaggtgat tggtttgtag gtgtaggcca cgtgaccggg 6001 tgttcctgaa ggggggctat aaaagggggt gggggcgcgt tcgtcctcac tctcttccgc 6061 atcgctgtct gcgagggcca gctgttgggg tgagtactcc ctctgaaaag cgggcatgac 6121 ttctgcgcta agattgtcag tttccaaaaa cgaggaggat ttgatattca cctggcccgc 6181 ggtgatgcct ttgagggtgg ccgcatccat ctggtcagaa aagacaatct ttttgttgtc

6241 aagcttggtg gcaaacgacc cgtagagggc gttggacagc aacttggcga tggagcgcag

6301 ggtttggttt ttgtcgcgat cggcgcgctc cttggccgcg atgtttagct gcacgtattc 6361 gcgcgcaacg caccgccatt cgggaaagac ggtggtgcgc tcgtcgggca ccaggtgcac

6421 gcgccaaccg cggttgtgca gggtgacaag gtcaacgctg gtggctacct ctccgcgtag

6481 gcgctcgttg gtccagcaga ggcggccgcc cttgcgcgag cagaatggcg gtagggggtc

6541 tagctgcgtc tcgtccgggg ggtctgcgtc cacggtaaag accccgggca gcaggcgcgc 6601 gtcgaagtag tctatcttgc atccttgcaa gtctagcgcc tgctgccatg cgcgggcggc

6661 aagcgcgcgc tcgtatgggt tgagtggggg accccatggc atggggtggg tgagcgcgga

6721 ggcgtacatg ccgcaaatgt cgtaaacgta gaggggctct ctgagtattc caagatatgt

6781 agggtagcat cttccaccgc ggatgctggc gcgcacgtaa tcgtatagtt cgtgcgaggg

6841 agcgaggagg tcgggaccga ggttgctacg ggcgggctgc tctgctcgga agactatctg 6901 cctgaagatg gcatgtgagt tggatgatat ggttggacgc tggaagacgt tgaagctggc

6961 gtctgtgaga cctaccgcgt cacgcacgaa ggaggcgtag gagtcgcgca gcttgttgac

7021 cagctcggcg gtgacctgca cgtctagggc gcagtagtcc agggtttcct tgatgatgtc

7081 atacttatcc tgtccctttt ttttccacag ctcgcggttg aggacaaact cttcgcggtc

7141 tttccagtac tcttggatcg gaaacccgtc ggcctccgaa cggtaagagc ctagcatgta 7201 gaactggttg acggcctggt aggcgcagca tcccttttct acgggtagcg cgtatgcctg

7261 cgcggccttc cggagcgagg tgtgggtgag cgcaaaggtg tccctgacca tgactttgag

7321 gtactggtat ttgaagtcag tgtcgtcgca tccgccctgc tcccagagca aaaagtccgt

7381 gcgctttttg gaacgcggat ttggcagggc gaaggtgaca tcgttgaaga gtatctttcc

7441 cgcgcgaggc ataaagttgc gtgtgatgcg gaagggtccc ggcacctcgg aacggttgtt 7501 aattacctgg gcggcgagca cgatctcgtc aaagccgttg atgttgtggc ccacaatgta

7561 aagttccaag aagcgcggga tgcccttgat ggaaggcaat tttttaagtt cctcgtaggt

7621 gagctcttca ggggagctga gcccgtgctc tgaaagggcc cagtctgcaa gatgagggtt

7681 ggaagcgacg aatgagctcc acaggtcacg ggccattagc atttgcaggt ggtcgcgaaa

7741 ggtcctaaac tggcgaccta tggccatttt ttctggggtg atgcagtaga aggtaagcgg 7801 gtcttgttcc cagcggtccc atccaaggtt cgcggctagg tctcgcgcgg cagtcactag

7861 aggctcatct ccgccgaact tcatgaccag catgaagggc acgagctgct tcccaaaggc

7921 ccccatccaa gtataggtct ctacatcgta ggtgacaaag agacgctcgg tgcgaggatg

7981 cgagccgatc gggaagaact ggatctcccg ccaccaattg gaggagtggc tattgatgtg

8041 gtgaaagtag aagtccctgc gacgggccga acactcgtgc tggcttttgt aaaaacgtgc 8101 gcagtactgg cagcggtgca cgggctgtac atcctgcacg aggttgacct gacgaccgcg

8161 cacaaggaag cagagtggga atttgagccc ctcgcctggc gggtttggct ggtggtcttc

8221 tacttcggct gcttgtcctt gaccgtctgg ctgctcgagg ggagttacgg tggatcggac

8281 caccacgccg cgcgagccca aagtccagat gtccgcgcgc ggcggtcgga gcttgatgac

8341 aacatcgcgc agatgggagc tgtccatggt ctggagctcc cgcggcgtca ggtcaggcgg 8401 gagctcctgc aggtttacct cgcatagacg ggtcagggcg cgggctagat ccaggtgata

8461 cctaatttcc aggggctggt tggtggcggc gtcgatggct tgcaagaggc cgcatccccg

8521 cggcgcgact acggtaccgc gcggcgggcg gtgggccgcg ggggtgtcct tggatgatgc

8581 atctaaaagc ggtgacgcgg gcgagccccc ggaggtaggg ggggctccgg acccgccggg

8641 agagggggca ggggcacgtc ggcgccgcgc gcgggcagga gctggtgctg cgcgcgtagg 8701 ttgctggcga acgcgacgac gcggcggttg atctcctgaa tctggcgcct ctgcgtgaag

8761 acgacgggcc cggtgagctt gagcctgaaa gagagttcga cagaatcaat ttcggtgtcg

8821 ttgacggcgg cctggcgcaa aatctcctgc acgtctcctg agttgtcttg ataggcgatc 8881 tcggccatga actgctcgat ctcttcctcc tggagatctc cgcgtccggc tcgctccacg

8941 gtggcggcga ggtcgttgga aatgcgggcc atgagctgcg agaaggcgtt gaggcctccc

9001 tcgttccaga cgcggctgta gaccacgccc ccttcggcat cgcgggcgcg catgaccacc

9061 tgcgcgagat tgagctccac gtgccgggcg aagacggcgt agtttcgcag gcgctgaaag 9121 aggtagttga gggtggtggc ggtgtgttct gccacgaaga agtacataac ccagcgtcgc

9181 aacgtggatt cgttgatatc ccccaaggcc tcaaggcgct ccatggcctc gtagaagtcc

9241 acggcgaagt tgaaaaactg ggagttgcgc gccgacacgg ttaactcctc ctccagaaga

9301 cggatgagct cggcgacagt gtcgcgcacc tcgcgctcaa aggctacagg ggcctcttct

9361 tcttcttcaa tctcctcttc cataagggcc tccccttctt cttcttctgg cggcggtggg 9421 ggagggggga cacggcggcg acgacggcgc accgggaggc ggtcgacaaa gcgctcgatc

9481 atctccccgc ggcgacggcg catggtctcg gtgacggcgc ggccgttctc gcgggggcgc

9541 agttggaaga cgccgcccgt catgtcccgg ttatgggttg gcggggggct gccatgcggc

9601 agggatacgg cgctaacgat gcatctcaac aattgttgtg taggtactcc gccgccgagg

9661 gacctgagcg agtccgcatc gaccggatcg gaaaacctct cgagaaaggc gtctaaccag 9721 tcacagtcgc aaggtaggct gagcaccgtg gcgggcggca gcgggcggcg gtcggggttg

9781 tttctggcgg aggtgctgct gatgatgtaa ttaaagtagg cggtcttgag acggcggatg

9841 gtcgacagaa gcaccatgtc cttgggtccg gcctgctgaa tgcgcaggcg gtcggccatg

9901 ccccaggctt cgttttgaca tcggcgcagg tctttgtagt agtcttgcat gagcctttct

9961 accggcactt cttcttctcc ttcctcttgt cctgcatctc ttgcatctat cgctgcggcg 10021 gcggcggagt ttggccgtag gtggcgccct cttcctccca tgcgtgtgac cccgaagccc

10081 ctcatcggct gaagcagggc taggtcggcg acaacgcgct cggctaatat ggcctgctgc

10141 acctgcgtga gggtagactg gaagtcatcc atgtccacaa agcggtggta tgcgcccgtg

10201 ttgatggtgt aagtgcagtt ggccataacg gaccagttaa cggtctggtg acccggctgc

10261 gagagctcgg tgtacctgag acgcgagtaa gccctcgagt caaatacgta gtcgttgcaa 10321 gtccgcacca ggtactggta tcccaccaaa aagtgcggcg gcggctggcg gtagaggggc

10381 cagcgtaggg tggccggggc tccgggggcg agatcttcca acataaggcg atgatatccg

10441 tagatgtacc tggacatcca ggtgatgccg gcggcggtgg tggaggcgcg cggaaagtcg

10501 cggacgcggt tccagatgtt gcgcagcggc aaaaagtgct ccatggtcgg gacgctctgg

10561 ccggtcaggc gcgcgcaatc gttgacgctc tagaccgtgc aaaaggagag cctgtaagcg 10621 ggcactcttc cgtggtctgg tggataaatt cgcaagggta tcatggcgga cgaccggggt

10681 tcgagccccg tatccggccg tccgccgtga tccatgcggt taccgcccgc gtgtcgaacc

10741 caggtgtgcg acgtcagaca acgggggagt gctccttttg gcttccttcc aggcgcggcg

10801 gctgctgcgc tagctttttt ggccactggc cgcgcgcagc gtaagcggtt aggctggaaa

10861 gcgaaagcat taagtggctc gctccctgta gccggagggt tattttccaa gggttgagtc 10921 gcgggacccc cggttcgagt ctcggaccgg ccggactgcg gcgaacgggg gtttgcctcc

10981 ccgtcatgca agaccccgct tgcaaattcc tccggaaaca gggacgagcc ccttttttgc

11041 ttttcccaga tgcatccggt gctgcggcag atgcgccccc ctcctcagca gcggcaagag

11101 caagagcagc ggcagacatg cagggcaccc tcccctcctc ctaccgcgtc aggaggggcg

11161 acatccgcgg ttgacgcggc agcagatggt gattacgaac ccccgcggcg ccgggcccgg 11221 cactacctgg acttggagga gggcgagggc ctggcgcggc taggagcgcc ctctcctgag

11281 cggtacccaa gggtgcagct gaagcgtgat acgcgtgagg cgtacgtgcc gcggcagaac

11341 ctgtttcgcg accgcgaggg agaggagccc gaggagatgc gggatcgaaa gttccacgca 11401 gggcgcgagc tgcggcatgg cctgaatcgc gagcggttgc tgcgcgagga ggactttgag

11461 cccgacgcgc gaaccgggat tagtcccgcg cgcgcacacg tggcggccgc cgacctggta

11521 accgcatacg agcagacggt gaaccaggag attaactttc aaaaaagctt taacaaccac

11581 gtgcgtacgc ttgtggcgcg cgaggaggtg gctataggac tgatgcatct gtgggacttt

11641 gtaagcgcgc tggagcaaaa cccaaatagc aagccgctca tggcgcagct gttccttata

11701 gtgcagcaca gcagggacaa cgaggcattc agggatgcgc tgctaaacat agtagagccc

11761 gagggccgct ggctgctcga tttgataaac atcctgcaga gcatagtggt gcaggagcgc

11821 agcttgagcc tggctgacaa ggtggccgcc atcaactatt ccatgcttag cctgggcaag

11881 ttttacgccc gcaagatata ccatacccct tacgttccca tagacaagga ggtaaagatc

11941 gaggggttct acatgcgcat ggcgctgaag gtgcttacct tgagcgacga cctgggcgtt

12001 tatcgcaacg agcgcatcca caaggccgtg agcgtgagcc ggcggcgcga gctcagcgac

12061 cgcgagctga tgcacagcct gcaaagggcc ctggctggca cgggcagcgg cgatagagag

12121 gccgagtcct actttgacgc gggcgctgac ctgcgctggg ccccaagccg acgcgccctg

12181 gaggcagctg gggccggacc tgggctggcg gtggcacccg cgcgcgctgg caacgtcggc

12241 ggcgtggagg aatatgacga ggacgatgag tacgagccag aggacggcga gtactaagcg

12301 gtgatgtttc tgatcagatg atgcaagacg caacggaccc ggcggtgcgg gcggcgctgc

12361 agagccagcc gtccggcctt aactccacgg acgactggcg ccaggtcatg gaccgcatca

12421 tgtcgctgac tgcgcgcaat cctgacgcgt tccggcagca gccgcaggcc aaccggctct

12481 ccgcaattct ggaagcggtg gtcccggcgc gcgcaaaccc cacgcacgag aaggtgctgg

12541 cgatcgtaaa cgcgctggcc gaaaacaggg ccatccggcc cgacgaggcc ggcctggtct

12601 acgacgcgct gcttcagcgc gtggctcgtt acaacagcgg caacgtgcag accaacctgg

12661 accggctggt gggggatgtg cgcgaggccg tggcgcagcg tgagcgcgcg cagcagcagg

12721 gcaacctggg ctccatggtt gcactaaacg ccttcctgag tacacagccc gccaacgtgc

12781 cgcggggaca ggaggactac accaactttg tgagcgcact gcggctaatg gtgactgaga

12841 caccgcaaag tgaggtgtac cagtctgggc cagactattt tttccagacc agtagacaag

12901 gcctgcagac cgtaaacctg agccaggctt tcaaaaactt gcaggggctg tggggggtgc

12961 gggctcccac aggcgaccgc gcgaccgtgt ctagcttgct gacgcccaac tcgcgcctgt

13021 tgctgctgct aatagcgccc ttcacggaca gtggcagcgt gtcccgggac acatacctag

13081 gtcacttgct gacactgtac cgcgaggcca taggtcaggc gcatgtggac gagcatactt

13141 tccaggagat tacaagtgtc agccgcgcgc tggggcagga ggacacgggc agcctggagg

13201 caaccctaaa ctacctgctg accaaccggc ggcagaagat cccctcgttg cacagtttaa

13261 acagcgagga ggagcgcatt ttgcgctacg tgcagcagag cgtgagcctt aacctgatgc

13321 gcgacggggt aacgcccagc gtggcgctgg acatgaccgc gcgcaacatg gaaccgggca

13381 tgtatgcctc aaaccggccg tttatcaacc gcctaatgga ctacttgcat cgcgcggccg

13441 ccgtgaaccc cgagtatttc accaatgcca tcttgaaccc gcactggcta ccgccccctg

13501 gtttctacac cgggggattc gaggtgcccg agggtaacga tggattcctc tgggacgaca

13561 tagacgacag cgtgttttcc ccgcaaccgc agaccctgct agagttgcaa cagcgcgagc

13621 aggcagaggc ggcgctgcga aaggaaagct tccgcaggcc aagcagcttg tccgatctag

13681 gcgctgcggc cccgcggtca gatgctagta gcccatttcc aagcttgata gggtctctta

13741 ccagcactcg caccacccgc ccgcgcctgc tgggcgagga ggagtaccta aacaactcgc

13801 tgctgcagcc gcagcgcgaa aaaaacctgc ctccggcatt tcccaacaac gggatagaga

13861 gcctagtgga caagatgagt agatggaaga cgtacgcgca ggagcacagg gacgtgccag 13921 gcccgcgccc gcccacccgt cgtcaaaggc acgaccgtca gcggggtctg gtgtgggagg

13981 acgatgactc ggcagacgac agcagcgtcc tggatttggg agggagtggc aacccgtttg

14041 cgcaccttcg ccccaggctg gggagaatgt tttaaaaaaa aaaaagcatg atgcaaaata

14101 aaaaactcac caaggccatg gcaccgagcg ttggttttct tgtattcccc ttagtatgcg

14161 gcgcgcggcg atgtatgagg aaggtcctcc tccctcctac gagagtgtgg tgagcgcggc

14221 gccagtggcg gcggcgctgg gttctccctt cgatgctccc ctggacccgc cgtttgtgcc

14281 tccgcggtac ctgcggccta ccggggggag aaacagcatc cgttactctg agttggcacc

14341 cctattcgac accacccgtg tgtacctggt ggacaacaag tcaacggatg tggcatccct

14401 gaactaccag aacgaccaca gcaactttct gaccacggtc attcaaaaca atgactacag

14461 cccgggggag gcaagcacac agaccatcaa tcttgacgac cggtcgcact ggggcggcga

14521 cctgaaaacc atcctgcata ccaacatgcc aaatgtgaac gagttcatgt ttaccaataa

14581 gtttaaggcg cgggtgatgg tgtcgcgctt gcctactaag gacaatcagg tggagctgaa

14641 atacgagtgg gtggagttca cgctgcccga gggcaactac tccgagacca tgaccataga

14701 ccttatgaac aacgcgatcg tggagcacta cttgaaagtg ggcagacaga acggggttct

14761 ggaaagcgac atcggggtaa agtttgacac ccgcaacttc agactggggt ttgaccccgt

14821 cactggtctt gtcatgcctg gggtatatac aaacgaagcc ttccatccag acatcatttt

14881 gctgccagga tgcggggtgg acttcaccca cagccgcctg agcaacttgt tgggcatccg

14941 caagcggcaa cccttccagg agggctttag gatcacctac gatgatctgg agggtggtaa

15001 cattcccgca ctgttggatg tggacgccta ccaggcgagc ttgaaagatg acaccgaaca

15061 gggcgggggt ggcgcaggcg gcagcaacag cagtggcagc ggcgcggaag agaactccaa

15121 cgcggcagcc gcggcaatgc agccggtgga ggacatgaac gatcatgcca ttcgcggcga

15181 cacctttgcc acacgggctg aggagaagcg cgctgaggcc gaagcagcgg ccgaagctgc

15241 cgcccccgct gcgcaacccg aggtcgagaa gcctcagaag aaaccggtga tcaaacccct

15301 gacagaggac agcaagaaac gcagttacaa cctaataagc aatgacagca ccttcaccca

15361 gtaccgcagc tggtaccttg catacaacta cggcgaccct cagaccggaa tccgctcatg

15421 gaccctgctt tgcactcctg acgtaacctg cggctcggag caggtctact ggtcgttgcc

15481 agacatgatg caagaccccg tgaccttccg ctccacgcgc cagatcagca actttccggt

15541 ggtgggcgcc gagctgttgc ccgtgcactc caagagcttc tacaacgacc aggccgtcta

15601 ctcccaactc atccgccagt ttacctctct gacccacgtg ttcaatcgct ttcccgagaa

15661 ccagattttg gcgcgcccgc cagcccccac catcaccacc gtcagtgaaa acgttcctgc

15721 tctcacagat cacgggacgc taccgctgcg caacagcatc ggaggagtcc agcgagtgac

15781 cattactgac gccagacgcc gcacctgccc ctacgtttac aaggccctgg gcatagtctc

15841 gccgcgcgtc ctatcgagcc gcactttttg agcaagcatg tccatcctta tatcgcccag

15901 caataacaca ggctggggcc tgcgcttccc aagcaagatg tttggcgggg ccaagaagcg

15961 ctccgaccaa cacccagtgc gcgtgcgcgg gcactaccgc gcgccctggg gcgcgcacaa

16021 acgcggccgc actgggcgca ccaccgtcga tgacgccatc gacgcggtgg tggaggaggc

16081 gcgcaactac acgcccacgc cgccaccagt gtccacagtg gacgcggcca ttcagaccgt

16141 ggtgcgcgga gcccggcgct atgctaaaat gaagagacgg cggaggcgcg tagcacgtcg

16201 ccaccgccgc cgacccggca ctgccgccca acgcgcggcg gcggccctgc ttaaccgcgc

16261 acgtcgcacc ggccgacggg cggccatgcg ggccgctcga aggctggccg cgggtattgt

16321 cactgtgccc cccaggtcca ggcgacgagc ggccgccgca gcagccgcgg ccattagtgc

16381 tatgactcag ggtcgcaggg gcaacgtgta ttgggtgcgc gactcggtta gcggcctgcg 16441 cgtgcccgtg cgcacccgcc ccccgcgcaa ctagattgca agaaaaaact acttagactc

16501 gtactgttgt atgtatccag cggcggcggc gcgcaacgaa gctatgtcca agcgcaaaat

16561 caaagaagag atgctccagg tcatcgcgcc ggagatctat ggccccccga agaaggaaga

16621 gcaggattac aagccccgaa agctaaagcg ggtcaaaaag aaaaagaaag atgatgatga

16681 tgaacttgac gacgaggtgg aactgctgca cgctaccgcg cccaggcgac gggtacagtg

16741 gaaaggtcga cgcgtaaaac gtgttttgcg acccggcacc accgtagtct ttacgcccgg

16801 tgagcgctcc acccgcacct acaagcgcgt gtatgatgag gtgtacggcg acgaggacct

16861 gcttgagcag gccaacgagc gcctcgggga gtttgcctac ggaaagcggc ataaggacat

16921 gctggcgttg ccgctggacg agggcaaccc aacacctagc ctaaagcccg taacactgca

16981 gcaggtgctg cccgcgcttg caccgtccga agaaaagcgc ggcctaaagc gcgagtctgg

17041 tgacttggca cccaccgtgc agctgatggt acccaagcgc cagcgactgg aagatgtctt

17101 ggaaaaaatg accgtggaac ctgggctgga gcccgaggtc cgcgtgcggc caatcaagca

17161 ggtggcgccg ggactgggcg tgcagaccgt ggacgttcag atacccacta ccagtagcac

17221 cagtattgcc accgccacag agggcatgga gacacaaacg tccccggttg cctcagcggt

17281 ggcggatgcc gcggtgcagg cggtcgctgc ggccgcgtcc aagacctcta cggaggtgca

17341 aacggacccg tggatgtttc gcgtttcagc cccccggcgc ccgcgcggtt cgaggaagta

17401 cggcgccgcc agcgcgctac tgcccgaata tgccctacat ccttccattg cgcctacccc

17461 cggctatcgt ggctacacct accgccccag aagacgagca actacccgac gccgaaccac

17521 cactggaacc cgccgccgcc gtcgccgtcg ccagcccgtg ctggccccga tttccgtgcg

17581 cagggtggct cgcgaaggag gcaggaccct ggtgctgcca acagcgcgct accaccccag

17641 catcgtttaa aagccggtct ttgtggttct tgcagatatg gccctcacct gccgcctccg

17701 tttcccggtg ccgggattcc gaggaagaat gcaccgtagg aggggcatgg ccggccacgg

17761 cctgacgggc ggcatgcgtc gtgcgcacca ccggcggcgg cgcgcgtcgc accgtcgcat

17821 gcgcggcggt atcctgcccc tccttattcc actgatcgcc gcggcgattg gcgccgtgcc

17881 cggaattgca tccgtggcct tgcaggcgca gagacactga ttaaaaacaa gttgcatgtg

17941 gaaaaatcaa aataaaaagt ctggactctc acgctcgctt ggtcctgtaa ctattttgta

18001 gaatggaaga catcaacttt gcgtctctgg ccccgcgaca cggctcgcgc ccgttcatgg

18061 gaaactggca agatatcggc accagcaata tgagcggtgg cgccttcagc tggggctcgc

18121 tgtggagcgg cattaaaaat ttcggttcca ccgttaagaa ctatggcagc aaggcctgga

18181 acagcagcac aggccagatg ctgagggata agttgaaaga gcaaaatttc caacaaaagg

18241 tggtagatgg cctggcctct ggcattagcg gggtggtgga cctggccaac caggcagtgc

18301 aaaataagat taacagtaag cttgatcccc gccctcccgt agaggagcct ccaccggccg

18361 tggagacagt gtctccagag gggcgtggcg aaaagcgtcc gcgccccgac agggaagaaa

18421 ctctggtgac gcaaatagac gagcctccct cgtacgagga ggcactaaag caaggcctgc

18481 ccaccacccg tcccatcgcg cccatggcta ccggagtgct gggccagcac acacccgtaa

18541 cgctggacct gcctcccccc gccgacaccc agcagaaacc tgtgctgcca ggcccgaccg

18601 ccgttgttgt aacccgtcct agccgcgcgt ccctgcgccg cgccgccagc ggtccgcgat

18661 cgttgcggcc cgtagccagt ggcaactggc aaagcacact gaacagcatc gtgggtctgg

18721 gggtgcaatc cctgaagcgc cgacgatgct tctgaatagc taacgtgtcg tatgtgtgtc

18781 atgtatgcgt ccatgtcgcc gccagaggag ctgctgagcc gccgcgcgcc cgctttccaa

18841 gatggctacc ccttcgatga tgccgcagtg gtcttacatg cacatctcgg gccaggacgc

18901 ctcggagtac ctgagccccg ggctggtgca gtttgcccgc gccaccgaga cgtacttcag 18961 cctgaataac aagtttagaa accccacggt ggcgcctacg cacgacgtga ccacagaccg

19021 gtcccagcgt ttgacgctgc ggttcatccc tgtggaccgt gaggatactg cgtactcgta

19081 caaggcgcgg ttcaccctag ctgtgggtga taaccgtgtg ctggacatgg cttccacgta

19141 ctttgacatc cgcggcgtgc tggacagggg ccctactttt aagccctact ctggcactgc

19201 ctacaacgcc ctggctccca agggtgcccc aaatccttgc gaatgggatg aagctgctac

19261 tgctcttgaa ataaacctag aagaagagga cgatgacaac gaagacgaag tagacgagca

19321 agctgagcag caaaaaactc acgtatttgg gcaggcgcct tattctggta taaatattac

19381 aaaggagggt attcaaatag gtgtcgaagg tcaaacacct aaatatgccg ataaaacatt

19441 tcaacctgaa cctcaaatag gagaatctca gtggtacgaa actgaaatta atcatgcagc

19501 tgggagagtc cttaaaaaga ctaccccaat gaaaccatgt tacggttcat atgcaaaacc

19561 cacaaatgaa aatggagggc aaggcattct tgtaaagcaa caaaatggaa agctagaaag

19621 tcaagtggaa atgcaatttt tctcaactac tgaggcgacc gcaggcaatg gtgataactt

19681 gactcctaaa gtggtattgt acagtgaaga tgtagatata gaaaccccag acactcatat

19741 ttcttacatg cccactatta aggaaggtaa ctcacgagaa ctaatgggcc aacaatctat

19801 gcccaacagg cctaattaca ttgcttttag ggacaatttt attggtctaa tgtattacaa

19861 cagcacgggt aatatgggtg ttctggcggg ccaagcatcg cagttgaatg ctgttgtaga

19921 tttgcaagac agaaacacag agctttcata ccagcttttg cttgattcca ttggtgatag

19981 aaccaggtac ttttctatgt ggaatcaggc tgttgacagc tatgatccag atgttagaat

20041 tattgaaaat catggaactg aagatgaact tccaaattac tgctttccac tgggaggtgt

20101 gattaataca gagactctta ccaaggtaaa acctaaaaca ggtcaggaaa atggatggga

20161 aaaagatgct acagaatttt cagataaaaa tgaaataaga gttggaaata attttgccat

20221 ggaaatcaat ctaaatgcca acctgtggag aaatttcctg tactccaaca tagcgctgta

20281 tttgcccgac aagctaaagt acagtccttc caacgtaaaa atttctgata acccaaacac

20341 ctacgactac atgaacaagc gagtggtggc tcccgggtta gtggactgct acattaacct

20401 tggagcacgc tggtcccttg actatatgga caacgtcaac ccatttaacc accaccgcaa

20461 tgctggcctg cgctaccgct caatgttgct gggcaatggt cgctatgtgc ccttccacat

20521 ccaggtgcct cagaagttct ttgccattaa aaacctcctt ctcctgccgg gctcatacac

20581 ctacgagtgg aacttcagga aggatgttaa catggttctg cagagctccc taggaaatga

20641 cctaagggtt gacggagcca gcattaagtt tgatagcatt tgcctttacg ccaccttctt

20701 ccccatggcc cacaacaccg cctccacgct tgaggccatg cttagaaacg acaccaacga

20761 ccagtccttt aacgactatc tctccgccgc caacatgctc taccctatac ccgccaacgc

20821 taccaacgtg cccatatcca tcccctcccg caactgggcg gctttccgcg gctgggcctt

20881 cacgcgcctt aagactaagg aaaccccatc actgggctcg ggctacgacc cttattacac

20941 ctactctggc tctataccct acctagatgg aaccttttac ctcaaccaca cctttaagaa

21001 ggtggccatt acctttgact cttctgtcag ctggcctggc aatgaccgcc tgcttacccc

21061 caacgagttt gaaattaagc gctcagttga cggggagggt tacaacgttg cccagtgtaa

21121 catgaccaaa gactggttcc tggtacaaat gctagctaac tacaacattg gctaccaggg

21181 cttctatatc ccagagagct acaaggaccg catgtactcc ttctttagaa acttccagcc

21241 catgagccgt caggtggtgg atgatactaa atacaaggac taccaacagg tgggcatcct

21301 acaccaacac aacaactctg gatttgttgg ctaccttgcc cccaccatgc gcgaaggaca

21361 ggcctaccct gctaacttcc cctatccgct tataggcaag accgcagttg acagcattac

21421 ccagaaaaag tttctttgcg atcgcaccct ttggcgcatc ccattctcca gtaactttat 21481 gtccatgggc gcactcacag acctgggcca aaaccttctc tacgccaact ccgcccacgc

21541 gctagacatg acttttgagg tggatcccat ggacgagccc acccttcttt atgttttgtt

21601 tgaagtcttt gacgtggtcc gtgtgcaccg gccgcaccgc ggcgtcatcg aaaccgtgta

21661 cctgcgcacg cccttctcgg ccggcaacgc cacaacataa agaagcaagc aacatcaaca

21721 acagctgccg ccatgggctc cagtgagcag gaactgaaag ccattgtcaa agatcttggt

21781 tgtgggccat attttttggg cacctatgac aagcgctttc caggctttgt ttctccacac

21841 aagctcgcct gcgccatagt caatacggcc ggtcgcgaga ctgggggcgt acactggatg

21901 gcctttgcct ggaacccgca ctcaaaaaca tgctacctct ttgagccctt tggcttttct

21961 gaccagcgac tcaagcaggt ttaccagttt gagtacgagt cactcctgcg ccgtagcgcc

22021 attgcttctt cccccgaccg ctgtataacg ctggaaaagt ccacccaaag cgtacagggg

22081 cccaactcgg ccgcctgtgg actattctgc tgcatgtttc tccacgcctt tgccaactgg

22141 ccccaaactc ccatggatca caaccccacc atgaacctta ttaccggggt acccaactcc

22201 atgctcaaca gtccccaggt acagcccacc ctgcgtcgca accaggaaca gctctacagc

22261 ttcctggagc gccactcgcc ctacttccgc agccacagtg cgcagattag gagcgccact

22321 tctttttgtc acttgaaaaa catgtaaaaa taatgtacta gagacacttt caataaaggc

22381 aaatgctttt atttgtacac tctcgggtga ttatttaccc ccacccttgc cgtctgcgcc

22441 gtttaaaaat caaaggggtt ctgccgcgca tcgctatgcg ccactggcag ggacacgttg

22501 cgatactggt gtttagtgct ccacttaaac tcaggcacaa ccatccgcgg cagctcggtg

22561 aagttttcac tccacaggct gcgcaccatc accaacgcgt ttagcaggtc gggcgccgat

22621 atcttgaagt cgcagttggg gcctccgccc tgcgcgcgcg agttgcgata cacagggttg

22681 cagcactgga acactatcag cgccgggtgg tgcacgctgg ccagcacgct cttgtcggag

22741 atcagatccg cgtccaggtc ctccgcgttg ctcagggcga acggagtcaa ctttggtagc

22801 tgccttccca aaaagggcgc gtgcccaggc tttgagttgc actcgcaccg tagtggcatc

22861 aaaaggtgac cgtgcccggt ctgggcgtta ggatacagcg cctgcataaa agccttgatc

22921 tgcttaaaag ccacctgagc ctttgcgcct tcagagaaga acatgccgca agacttgccg

22981 gaaaactgat tggccggaca ggccgcgtcg tgcacgcagc accttgcgtc ggtgttggag

23041 atctgcacca catttcggcc ccaccggttc ttcacgatct tggccttgct agactgctcc

23101 ttcagcgcgc gctgcccgtt ttcgctcgtc acatccattt caatcacgtg ctccttattt

23161 atcataatgc ttccgtgtag acacttaagc tcgccttcga tctcagcgca gcggtgcagc

23221 cacaacgcgc agcccgtggg ctcgtgatgc ttgtaggtca cctctgcaaa cgactgcagg

23281 tacgcctgca ggaatcgccc catcatcgtc acaaaggtct tgttgctggt gaaggtcagc

23341 tgcaacccgc ggtgctcctc gttcagccag gtcttgcata cggccgccag agcttccact

23401 tggtcaggca gtagtttgaa gttcgccttt agatcgttat ccacgtggta cttgtccatc

23461 agcgcgcgcg cagcctccat gcccttctcc cacgcagaca cgatcggcac actcagcggg

23521 ttcatcaccg taatttcact ttccgcttcg ctgggctctt cctcttcctc ttgcgtccgc

23581 ataccacgcg ccactgggtc gtcttcattc agccgccgca ctgtgcgctt acctcctttg

23641 ccatgcttga ttagcaccgg tgggttgctg aaacccacca tttgtagcgc cacatcttct

23701 ctttcttcct cgctgtccac gattacctct ggtgatggcg ggcgctcggg cttgggagaa

23761 gggcgcttct ttttcttctt gggcgcaatg gccaaatccg ccgccgaggt cgatggccgc

23821 gggctgggtg tgcgcggcac cagcgcgtct tgtgatgagt cttcctcgtc ctcggactcg

23881 atacgccgcc tcatccgctt ttttgggggc gcccggggag gcggcggcga cggggacggg

23941 gacgacacgt cctccatggt tgggggacgt cgcgccgcac cgcgtccgcg ctcgggggtg 24001 gtttcgcgct gctcctcttc ccgactggcc atttccttct cctataggca gaaaaagatc

24061 atggagtcag tcgagaagaa ggacagccta accgccccct ctgagttcgc caccaccgcc

24121 tccaccgatg ccgccaacgc gcctaccacc ttccccgtcg aggcaccccc gcttgaggag

24181 gaggaagtga ttatcgagca ggacccaggt tttgtaagcg aagacgacga ggaccgctca

24241 gtaccaacag aggataaaaa gcaagaccag gacaacgcag aggcaaacga ggaacaagtc

24301 gggcgggggg acgaaaggca tggcgactac ctagatgtgg gagacgacgt gctgttgaag

24361 catctgcagc gccagtgcgc cattatctgc gacgcgttgc aagagcgcag cgatgtgccc

24421 ctcgccatag cggatgtcag ccttgcctac gaacgccacc tattctcacc gcgcgtaccc

24481 cccaaacgcc aagaaaacgg cacatgcgag cccaacccgc gcctcaactt ctaccccgta

24541 tttgccgtgc cagaggtgct tgccacctat cacatctttt tccaaaactg caagataccc

24601 ctatcctgcc gtgccaaccg cagccgagcg gacaagcagc tggccttgcg gcagggcgct

24661 gtcatacctg atatcgcctc gctcaacgaa gtgccaaaaa tctttgaggg tcttggacgc

24721 gacgagaagc gcgcggcaaa cgctctgcaa caggaaaaca gcgaaaatga aagtcactct

24781 ggagtgttgg tggaactcga gggtgacaac gcgcgcctag ccgtactaaa acgcagcatc

24841 gaggtcaccc actttgccta cccggcactt aacctacccc ccaaggtcat gagcacagtc

24901 atgagtgagc tgatcgtgcg ccgtgcgcag cccctggaga gggatgcaaa tttgcaagaa

24961 caaacagagg agggcctacc cgcagttggc gacgagcagc tagcgcgctg gcttcaaacg

25021 cgcgagcctg ccgacttgga ggagcgacgc aaactaatga tggccgcagt gctcgttacc

25081 gtggagcttg agtgcatgca gcggttcttt gctgacccgg agatgcagcg caagctagag

25141 gaaacattgc actacacctt tcgacagggc tacgtacgcc aggcctgcaa gatctccaac

25201 gtggagctct gcaacctggt ctcctacctt ggaattttgc acgaaaaccg ccttgggcaa

25261 aacgtgcttc attccacgct caagggcgag gcgcgccgcg actacgtccg cgactgcgtt

25321 tacttatttc tatgctacac ctggcagacg gccatgggcg tttggcagca gtgcttggag

25381 gagtgcaacc tcaaggagct gcagaaactg ctaaagcaaa acttgaagga cctatggacg

25441 gccttcaacg agcgctccgt ggccgcgcac ctggcggaca tcattttccc cgaacgcctg

25501 cttaaaaccc tgcaacaggg tctgccagac ttcaccagtc aaagcatgtt gcagaacttt

25561 aggaacttta tcctagagcg ctcaggaatc ttgcccgcca cctgctgtgc acttcctagc

25621 gactttgtgc ccattaagta ccgcgaatgc cctccgccgc tttggggcca ctgctacctt

25681 ctgcagctag ccaactacct tgcctaccac tctgacataa tggaagacgt gagcggtgac

25741 ggtctactgg agtgtcactg tcgctgcaac ctatgcaccc cgcaccgctc cctggtttgc

25801 aattcgcagc tgcttaacga aagtcaaatt atcggtacct ttgagctgca gggtccctcg

25861 cctgacgaaa agtccgcggc tccggggttg aaactcactc cggggctgtg gacgtcggct

25921 taccttcgca aatttgtacc tgaggactac cacgcccacg agattaggtt ctacgaagac

25981 caatcccgcc cgccaaatgc ggagcttacc gcctgcgtca ttacccaggg ccacattctt

26041 ggccaattgc aagccatcaa caaagcccgc caagagtttc tgctacgaaa gggacggggg

26101 gtttacttgg acccccagtc cggcgaggag ctcaacccaa tccccccgcc gccgcagccc

26161 tatcagcagc agccgcgggc ccttgcttcc caggatggca cccaaaaaga agctgcagct

26221 gccgccgcca cccacggacg aggaggaata ctgggacagt caggcagagg aggttttgga

26281 cgaggaggag gaggacatga tggaagactg ggagagccta gacgaggaag cttccgaggt

26341 cgaagaggtg tcagacgaaa caccgtcacc ctcggtcgca ttcccctcgc cggcgcccca

26401 gaaatcggca accggttcca gcatggctac aacctccgct cctcaggcgc cgccggcact

26461 gcccgttcgc cgacccaacc gtagatggga caccactgga accagggccg gtaagtccaa 26521 gcagccgccg ccgttagccc aagagcaaca acagcgccaa ggctaccgct catggcgcgg

26581 gcacaagaac gccatagttg cttgcttgca agactgtggg ggcaacatct ccttcgcccg

26641 ccgctttctt ctctaccatc acggcgtggc cttcccccgt aacatcctgc attactaccg

26701 tcatctctac agcccatact gcaccggcgg cagcggcagc ggcagcaaca gcagcggcca

26761 cacagaagca aaggcgaccg gatagcaaga ctctgacaaa gcccaagaaa tccacagcgg

26821 cggcagcagc aggaggagga gcgctgcgtc tggcgcccaa cgaacccgta tcgacccgcg

26881 agcttagaaa caggattttt cccactctgt atgctatatt tcaacagagc aggggccaag

26941 aacaagagct gaaaataaaa aacaggtctc tgcgatccct cacccgcagc tgcctgtatc

27001 acaaaagcga agatcagctt cggcgcacgc tggaagacgc ggaggctctc ttcagtaaat

27061 actgcgcgct gactcttaag gactagtttc gcgccctttc tcaaatttaa gcgcgaaaac

27121 tacgtcatct ccagcggcca cacccggcgc cagcacctgt cgtcagcgcc attatgagca

27181 aggaaattcc cacgccctac atgtggagtt accagccaca aatgggactt gcggctggag

27241 ctgcccaaga ctactcaacc cgaataaact acatgagcgc gggaccccac atgatatccc

27301 gggtcaacgg aatccgcgcc caccgaaacc gaattctctt ggaacaggcg gctattacca

27361 ccacacctcg taataacctt aatccccgta gttggcccgc tgccctggtg taccaggaaa

27421 gtcccgctcc caccactgtg gtacttccca gagacgccca ggccgaagtt cagatgacta

27481 actcaggggc gcagcttgcg ggcggctttc gtcacagggt gcggtcgccc gggcagggta

27541 taactcacct gacaatcaga gggcgaggta ttcagctcaa cgacgagtcg gtgagctcct

27601 cgcttggtct ccgtccggac gggacatttc agatcggcgg cgccggccgt ccttcattca

27661 cgcctcgtca ggcaatccta actctgcaga cctcgtcctc tgagccgcgc tctggaggca

27721 ttggaactct gcaatttatt gaggagtttg tgccatcggt ctactttaac cccttctcgg

27781 gacctcccgg ccactatccg gatcaattta ttcctaactt tgacgcggta aaggactcgg

27841 cggacggcta cgactgaatg ttaagtggag aggcagagca actgcgcctg aaacacctgg

27901 tccactgtcg ccgccacaag tgctttgccc gcgactccgg tgagttttgc tactttgaat

27961 tgcccgagga tcatatcgag ggcccggcgc acggcgtccg gcttaccgcc cagggagagc

28021 ttgcccgtag cctgattcgg gagtttaccc agcgccccct gctagttgag cgggacaggg

28081 gaccctgtgt tctcactgtg atttgcaact gtcctaacct tggattacat caagatcttt

28141 gttgccatct ctgtgctgag tataataaat acagaaatta aaatatactg gggctcctat

28201 cgccatcctg taaacgccac cgtcttcacc cgcccaagca aaccaaggcg aaccttacct

28261 ggtactttta acatctctcc ctctgtgatt tacaacagtt tcaacccaga cggagtgagt

28321 ctacgagaga acctctccga gctcagctac tccatcagaa aaaacaccac cctccttacc

28381 tgccgggaac gtacgagtgc gtcaccggcc gctgcaccac acctaccgcc tgaccgtaaa

28441 ccagactttt tccggacaga cctcaataac tctgtttacc agaacaggag gtgagcttag

28501 aaaaccctta gggtattagg ccaaaggcgc agctactgtg gggtttatga acaattcaag

28561 caactctacg ggctattcta attcaggttt ctctagaatc ggggttgggg ttattctctg

28621 tcttgtgatt ctctttattc ttatactaac gcttctctgc ctaaggctcg ccgcctgctg

28681 tgtgcacatt tgcatttatt gtcagctttt taaacgctgg ggtcgccacc caagatgatt

28741 aggtacataa tcctaggttt actcaccctt gcgtcagccc acggtaccac ccaaaaggtg

28801 gattttaagg agccagcctg taatgttaca ttcgcagctg aagctaatga gtgcaccact

28861 cttataaaat gcaccacaga acatgaaaag ctgcttattc gccacaaaaa caaaattggc

28921 aagtatgctg tttatgctat ttggcagcca ggtgacacta cagagtataa tgttacagtt

28981 ttccagggta aaagtcataa aacttttatg tatacttttc cattttatga aatgtgcgac 29041 attaccatgt acatgagcaa acagtataag ttgtggcccc cacaaaattg tgtggaaaac

29101 actggcactt tctgctgcac tgctatgcta attacagtgc tcgctttggt ctgtacccta

29161 ctctatatta aatacaaaag cagacgcagc tttattgagg aaaagaaaat gccttaattt

29221 actaagttac aaagctaatg tcaccactaa ctgctttact cgctgcttgc aaaacaaatt

29281 caaaaagtta gcattataat tagaatagga tttaaacccc ccggtcattt cctgctcaat

29341 accattcccc tgaacaattg actctatgtg ggatatgctc cagcgctaca accttgaagt

29401 caggcttcct ggatgtcagc atctgacttt ggccagcacc tgtcccgcgg atttgttcca

29461 gtccaactac agcgacccac cctaacagag atgaccaaca caaccaacgc ggccgccgct

29521 accggactta catctaccac aaatacaccc caagtttctg cctttgtcaa taactgggat

29581 aacttgggca tgtggtggtt ctccatagcg cttatgtttg tatgccttat tattatgtgg

29641 ctcatctgct gcctaaagcg caaacgcgcc cgaccaccca tctatagtcc catcattgtg

29701 ctacacccaa acaatgatgg aatccataga ttggacggac tgaaacacat gttcttttct

29761 cttacagtat gattaaatga gacatgattc ctcgagtttt tatattactg acccttgttg

29821 cgcttttttg tgcgtgctcc acattggctg cggtttctca catcgaagta gactgcattc

29881 cagccttcac agtctatttg ctttacggat ttgtcaccct cacgctcatc tgcagcctca

29941 tcactgtggt catcgccttt atccagtgca ttgactgggt ctgtgtgcgc tttgcatatc

30001 tcagacacca tccccagtac agggacagga ctatagctga gcttcttaga attctttaat

30061 tatgaaattt actgtgactt ttctgctgat tatttgcacc ctatctgcgt tttgttcccc

30121 gacctccaag cctcaaagac atatatcatg cagattcact cgtatatgga atattccaag

30181 ttgctacaat gaaaaaagcg atctttccga agcctggtta tatgcaatca tctctgttat

30241 ggtgttctgc agtaccatct tagccctagc tatatatccc taccttgaca ttggctggaa

30301 acgaatagat gccatgaacc acccaacttt ccccgcgccc gctatgcttc cactgcaaca

30361 agttgttgcc ggcggctttg tcccagccaa tcagcctcgc cccacttctc ccacccccac

30421 tgaaatcagc tactttaatc taacaggagg agatgactga caccctagat ctagaaatgg

30481 acggaattat tacagagcag cgcctgctag aaagacgcag ggcagcggcc gagcaacagc

30541 gcatgaatca agagctccaa gacatggtta acttgcacca gtgcaaaagg ggtatctttt

30601 gtctggtaaa gcaggccaaa gtcacctacg acagtaatac caccggacac cgccttagct

30661 acaagttgcc aaccaagcgt cagaaattgg tggtcatggt gggagaaaag cccattacca

30721 taactcagca ctcggtagaa accgaaggct gcattcactc accttgtcaa ggacctgagg

30781 atctctgcac ccttattaag accctgtgcg gtctcaaaga tcttattccc tttaactaat

30841 aaaaaaaaat aataaagcat cacttactta aaatcagtta gcaaatttct gtccagttta

30901 ttcagcagca cctccttgcc ctcctcccag ctctggtatt gcagcttcct cctggctgca

30961 aactttctcc acaatctaaa tggaatgtca gtttcctcct gttcctgtcc atccgcaccc

31021 actatcttca tgttgttgca gatgaagcgc gcaagaccgt ctgaagatac cttcaacccc

31081 gtgtatccat atgacacgga aaccggtcct ccaactgtgc cttttcttac tcctcccttt

31141 gtatccccca atgggtttca agagagtccc cctggggtac tctctttgcg cctatccgaa

31201 cctctagtta cctccaatgg catgcttgcg ctcaaaatgg gcaacggcct ctctctggac

31261 gaggccggca accttacctc ccaaaatgta accactgtga gcccacctct caaaaaaacc

31321 aagtcaaaca taaacctgga aatatctgca cccctcacag ttacctcaga agccctaact

31381 gtggctgccg ccgcacctct aatggtcgcg ggcaacacac tcaccatgca atcacaggcc

31441 ccgctaaccg tgcacgactc caaacttagc attgccaccc aaggacccct cacagtgtca

31501 gaaggaaagc tagccctgca aacatcaggc cccctcacca ccaccgatag cagtaccctt 31561 actatcactg cctcaccccc tctaactact gccactggta gcttgggcat tgacttgaaa

31621 gagcccattt atacacaaaa tggaaaacta ggactaaagt acggggctcc tttgcatgta

31681 acagacgacc taaacacttt gaccgtagca actggtccag gtgtgactat taataatact

31741 tccttgcaaa ctaaagttac tggagccttg ggttttgatt cacaaggcaa tatgcaactt

31801 aatgtagcag gaggactaag gattgattct caaaacagac gccttatact tgatgttagt

31861 tatccgtttg atgctcaaaa ccaactaaat ctaagactag gacagggccc tctttttata

31921 aactcagccc acaacttgga tattaactac aacaaaggcc tttacttgtt tacagcttca

31981 aacaattcca aaaagcttga ggttaaccta agcactgcca aggggttgat gtttgacgct

32041 acagccatag ccattaatgc aggagatggg cttgaatttg gttcacctaa tgcaccaaac

32101 acaaatcccc tcaaaacaaa aattggccat ggcctagaat ttgattcaaa caaggctatg

32161 gttcctaaac taggaactgg ccttagtttt gacagcacag gtgccattac agtaggaaac

32221 aaaaataatg ataagctaac tttgtggacc acaccagctc catctcctaa ctgtagacta

32281 aatgcagaga aagatgctaa actcactttg gtcttaacaa aatgtggcag tcaaatactt

32341 gctacagttt cagttttggc tgttaaaggc agtttggctc caatatctgg aacagttcaa

32401 agtgctcatc ttattataag atttgacgaa aatggagtgc tactaaacaa ttccttcctg

32461 gacccagaat attggaactt tagaaatgga gatcttactg aaggcacagc ctatacaaac

32521 gctgttggat ttatgcctaa cctatcagct tatccaaaat ctcacggtaa aactgccaaa

32581 agtaacattg tcagtcaagt ttacttaaac ggagacaaaa ctaaacctgt aacactaacc

32641 attacactaa acggtacaca ggaaacagga gacacaactc caagtgcata ctctatgtca

32701 ttttcatggg actggtctgg ccacaactac attaatgaaa tatttgccac atcctcttac

32761 actttttcat acattgccca agaataaaga atcgtttgtg ttatgtttca acgtgtttat

32821 ttttcaattg cagaaaattt caagtcattt ttcattcagt agtatagccc caccaccaca

32881 tagcttatac agatcaccgt accttaatca aactcacaga accctagtat tcaacctgcc

32941 acctccctcc caacacacag agtacacagt cctttctccc cggctggcct taaaaagcat

33001 catatcatgg gtaacagaca tattcttagg tgttatattc cacacggttt cctgtcgagc

33061 caaacgctca tcagtgatat taataaactc cccgggcagc tcacttaagt tcatgtcgct

33121 gtccagctgc tgagccacag gctgctgtcc aacttgcggt tgcttaacgg gcggcgaagg

33181 agaagtccac gcctacatgg gggtagagtc ataatcgtgc atcaggatag ggcggtggtg

33241 ctgcagcagc gcgcgaataa actgctgccg ccgccgctcc gtcctgcagg aatacaacat

33301 ggcagtggtc tcctcagcga tgattcgcac cgcccgcagc ataaggcgcc ttgtcctccg

33361 ggcacagcag cgcaccctga tctcacttaa atcagcacag taactgcagc acagcaccac

33421 aatattgttc aaaatcccac agtgcaaggc gctgtatcca aagctcatgg cggggaccac

33481 agaacccacg tggccatcat accacaagcg caggtagatt aagtggcgac ccctcataaa

33541 cacgctggac ataaacatta cctcttttgg catgttgtaa ttcaccacct cccggtacca

33601 tataaacctc tgattaaaca tggcgccatc caccaccatc ctaaaccagc tggccaaaac

33661 ctgcccgccg gctatacact gcagggaacc gggactggaa caatgacagt ggagagccca

33721 ggactcgtaa ccatggatca tcatgctcgt catgatatca atgttggcac aacacaggca

33781 cacgtgcata cacttcctca ggattacaag ctcctcccgc gttagaacca tatcccaggg

33841 aacaacccat tcctgaatca gcgtaaatcc cacactgcag ggaagacctc gcacgtaact

33901 cacgttgtgc attgtcaaag tgttacattc gggcagcagc ggatgatcct ccagtatggt

33961 agcgcgggtt tctgtctcaa aaggaggtag acgatcccta ctgtacggag tgcgccgaga

34021 caaccgagat cgtgttggtc gtagtgtcat gccaaatgga acgccggacg tagtcatatt 34081 tcctgaagca aaaccaggtg cgggcgtgac aaacagatct gcgtctccgg tctcgccgct

34141 tagatcgctc tgtgtagtag ttgtagtata tccactctct caaagcatcc aggcgccccc

34201 tggcttcggg ttctatgtaa actccttcat gcgccgctgc cctgataaca tccaccaccg

34261 cagaataagc cacacccagc caacctacac attcgttctg cgagtcacac acgggaggag

34321 cgggaagagc tggaagaacc atgttttttt ttttattcca aaagattatc caaaacctca

34381 aaatgaagat ctattaagtg aacgcgctcc cctccggtgg cgtggtcaaa ctctacagcc

34441 aaagaacaga taatggcatt tgtaagatgt tgcacaatgg cttccaaaag gcaaacggcc

34501 ctcacgtcca agtggacgta aaggctaaac ccttcagggt gaatctcctc tataaacatt

34561 ccagcacctt caaccatgcc caaataattc tcatctcgcc accttctcaa tatatctcta

34621 agcaaatccc gaatattaag tccggccatt gtaaaaatct gctccagagc gccctccacc

34681 ttcagcctca agcagcgaat catgattgca aaaattcagg ttcctcacag acctgtataa

34741 gattcaaaag cggaacatta acaaaaatac cgcgatcccg taggtccctt cgcagggcca

34801 gctgaacata atcgtgcagg tctgcacgga ccagcgcggc cacttccccg ccaggaacca

34861 tgacaaaaga acccacactg attatgacac gcatactcgg agctatgcta accagcgtag

34921 ccccgatgta agcttgttgc atgggcggcg atataaaatg caaggtgctg ctcaaaaaat

34981 caggcaaagc ctcgcgcaaa aaagaaagca catcgtagtc atgctcatgc agataaaggc 35041 aggtaagctc cggaaccacc acagaaaaag acaccatttt tctctcaaac atgtctgcgg 35101 gtttctgcat aaacacaaaa taaaataaca aaaaaacatt taaacattag aagcctgtct 35161 tacaacagga aaaacaaccc ttataagcat aagacggact acggccatgc cggcgtgacc 35221 gtaaaaaaac tggtcaccgt gattaaaaag caccaccgac agctcctcgg tcatgtccgg 35281 agtcataatg taagactcgg taaacacatc aggttgattc acatcggtca gtgctaaaaa 35341 gcgaccgaaa tagcccgggg gaatacatac ccgcaggcgt agagacaaca ttacagcccc 35401 cataggaggt ataacaaaat taataggaga gaaaaacaca taaacacctg aaaaaccctc 35461 ctgcctaggc aaaatagcac cctcccgctc cagaacaaca tacagcgctt ccacagcggc 35521 agccataaca gtcagcctta ccagtaaaaa agaaaaccta ttaaaaaaac accactcgac 35581 acggcaccag ctcaatcagt cacagtgtaa aaaagggcca agtgcagagc gagtatatat

35641 aggactaaaa aatgacgtaa cggttaaagt ccacaaaaaa cacccagaaa accgcacgcg 35701 aacctacgcc cagaaacgaa agccaaaaaa cccacaactt cctcaaatcg tcacttccgt 35761 tttcccacgt tacgtaactt cccattttaa gaaaactaca attcccaaca catacaagtt 35821 actccgccct aaaacctacg tcacccgccc cgttcccacg ccccgcgcca cgtcacaaac 35881 tccaccccct cattatcata ttggcttcaa tccaaaataa ggtatattat tgatgatg

SEQ ID NO: 47 (L4-100K)

ATGGAGTCAGTCGAGAAGAAGGACAGCCTAACCGCCCCCTCTGAGTTCGCCACCACC GCCT CCACCGATGCCGCCAACGCGCCTACCACCTTCCCCGTCGAGGCACCCCCGCTTGAGGAGG A GGAAGTGATTATCGAGCAGGACCCAGGTTTTGTAAGCGAAGACGACGAGGACCGCTCAGT A CCAACAGAGGATAAAAAGCAAGACCAGGACAACGCAGAGGCAAACGAGGAACAAGTCGGG C GGGGGGACGAAAGGCATGGCGACTACCTAGATGTGGGAGACGACGTGCTGTTGAAGCATC T GCAGCGCCAGTGCGCCATTATCTGCGACGCGTTGCAAGAGCGCAGCGATGTGCCCCTCGC C ATAGCGGATGTCAGCCTTGCCTACGAACGCCACCTATTCTCACCGCGCGTACCCCCCAAA C GCCAAGAAAACGGCACATGCGAGCCCAACCCGCGCCTCAACTTCTACCCCGTATTTGCCG T GCCAGAGGTGCTTGCCACCTATCACATCTTTTTCCAAAACTGCAAGATACCCCTATCCTG C CGTGCCAACCGCAGCCGAGCGGACAAGCAGCTGGCCTTGCGGCAGGGCGCTGTCATACCT G ATATCGCCTCGCTCAACGAAGTGCCAAAAATCTTTGAGGGTCTTGGACGCGACGAGAAGC G CGCGGCAAACGCTCTGCAACAGGAAAACAGCGAAAATGAAAGTCACTCTGGAGTGTTGGT G GAACTCGAGGGTGACAACGCGCGCCTAGCCGTACTAAAACGCAGCATCGAGGTCACCCAC T TTGCCTACCCGGCACTTAACCTACCCCCCAAGGTCATGAGCACAGTCATGAGTGAGCTGA T CGTGCGCCGTGCGCAGCCCCTGGAGAGGGATGCAAATTTGCAAGAACAAACAGAGGAGGG C CTACCCGCAGTTGGCGACGAGCAGCTAGCGCGCTGGCTTCAAACGCGCGAGCCTGCCGAC T TGGAGGAGCGACGCAAACTAATGATGGCCGCAGTGCTCGTTACCGTGGAGCTTGAGTGCA T GCAGCGGTTCTTTGCTGACCCGGAGATGCAGCGCAAGCTAGAGGAAACATTGCACTACAC C TTTCGACAGGGCTACGTACGCCAGGCCTGCAAGATCTCCAACGTGGAGCTCTGCAACCTG G TCTCCTACCTTGGAATTTTGCACGAAAACCGCCTTGGGCAAAACGTGCTTCATTCCACGC T CAAGGGCGAGGCGCGCCGCGACTACGTCCGCGACTGCGTTTACTTATTTCTATGCTACAC C TGGCAGACGGCCATGGGCGTTTGGCAGCAGTGCTTGGAGGAGTGCAACCTCAAGGAGCTG C AGAAACTGCTAAAGCAAAACTTGAAGGACCTATGGACGGCCTTCAACGAGCGCTCCGTGG C CGCGCACCTGGCGGACATCATTTTCCCCGAACGCCTGCTTAAAACCCTGCAACAGGGTCT G CCAGACTTCACCAGTCAAAGCATGTTGCAGAACTTTAGGAACTTTATCCTAGAGCGCTCA G GAATCTTGCCCGCCACCTGCTGTGCACTTCCTAGCGACTTTGTGCCCATTAAGTACCGCG A ATGCCCTCCGCCGCTTTGGGGCCACTGCTACCTTCTGCAGCTAGCCAACTACCTTGCCTA C CACTCTGACATAATGGAAGACGTGAGCGGTGACGGTCTACTGGAGTGTCACTGTCGCTGC A ACCTATGCACCCCGCACCGCTCCCTGGTTTGCAATTCGCAGCTGCTTAACGAAAGTCAAA T TATCGGTACCTTTGAGCTGCAGGGTCCCTCGCCTGACGAAAAGTCCGCGGCTCCGGGGTT G AAACTCACTCCGGGGCTGTGGACGTCGGCTTACCTTCGCAAATTTGTACCTGAGGACTAC C ACGCCCACGAGATTAGGTTCTACGAAGACCAATCCCGCCCGCCAAATGCGGAGCTTACCG C CTGCGTCATTACCCAGGGCCACATTCTTGGCCAATTGCAAGCCATCAACAAAGCCCGCCA A GAGTTTCTGCTACGAAAGGGACGGGGGGTTTACTTGGACCCCCAGTCCGGCGAGGAGCTC A ACCCAATCCCCCCGCCGCCGCAGCCCTATCAGCAGCAGCCGCGGGCCCTTGCTTCCCAGG A TGGCACCCAAAAAGAAGCTGCAGCTGCCGCCGCCACCCACGGACGAGGAGGAATACTGGG A CAGTCAGGCAGAGGAGGTTTTGGACGAGGAGGAGGAGGACATGATGGAAGACTGGGAGAG C CTAGACGAGGAAGCTTCCGAGGTCGAAGAGGTGTCAGACGAAACACCGTCACCCTCGGTC G CATTCCCCTCGCCGGCGCCCCAGAAATCGGCAACCGGTTCCAGCATGGCTACAACCTCCG C TCCTCAGGCGCCGCCGGCACTGCCCGTTCGCCGACCCAACCGTAG

SEQ ID NO: 48 (52/55K)

ATGCATCCGGTGCTGCGGCAGATGCGCCCCCCTCCTCAGCAGCGGCAAGAGCAAGAG CAGC GGCAGACATGCAGGGCACCCTCCCCTCCTCCTACCGCGTCAGGAGGGGCGACATCCGCGG T TGACGCGGCAGCAGATGGTGATTACGAACCCCCGCGGCGCCGGGCCCGGCACTACCTGGA C TTGGAGGAGGGCGAGGGCCTGGCGCGGCTAGGAGCGCCCTCTCCTGAGCGGCACCCAAGG G TGCAGCTGAAGCGTGATACGCGTGAGGCGTACGTGCCGCGGCAGAACCTGTTTCGCGACC G CGAGGGAGAGGAGCCCGAGGAGATGCGGGATCGAAAGTTCCACGCAGGGCGCGAGCTGCG G CATGGCCTGAATCGCGAGCGGTTGCTGCGCGAGGAGGACTTTGAGCCCGACGCGCGAACC G GGATTAGTCCCGCGCGCGCACACGTGGCGGCCGCCGACCTGGTAACCGCATACGAGCAGA C GGTGAACCAGGAGATTAACTTTCAAAAAAGCTTTAACAACCACGTGCGTACGCTTGTGGC G CGCGAGGAGGTGGCTATAGGACTGATGCATCTGTGGGACTTTGTAAGCGCGCTGGAGCAA A ACCCAAATAGCAAGCCGCTCATGGCGCAGCTGTTCCTTATAGTGCAGCACAGCAGGGACA A CGAGGCATTCAGGGATGCGCTGCTAAACATAGTAGAGCCCGAGGGCCGCTGGCTGCTCGA T TTGATAAACATCCTGCAGAGCATAGTGGTGCAGGAGCGCAGCTTGAGCCTGGCTGACAAG G TGGCCGCCATCAACTATTCCATGCTTAGCCTGGGCAAGTTTTACGCCCGCAAGATATACC A TACCCCTTACGTTCCCATAGACAAGGAGGTAAAGATCGAGGGGTTCTACATGCGCATGGC G CTGAAGGTGCTTACCTTGAGCGACGACCTGGGCGTTTATCGCAACGAGCGCATCCACAAG G CCGTGAGCGTGAGCCGGCGGCGCGAGCTCAGCGACCGCGAGCTGATGCACAGCCTGCAAA G GGCCCTGGCTGGCACGGGCAGCGGCGATAGAGAGGCCGAGTCCTACTTTGACGCGGGCGC T GACCTGCGCTGGGCCCCAAGCCGACGCGCCCTGGAGGCAGCTGGGGCCGGACCTGGGCTG G CGGTGGCACCCGCGCGCGCTGGCAACGTCGGCGGCGTGGAGGAATATGACGAGGACGATG A GTACGAGCCAGAGGACGGCGAGTACTAA

SEQ ID NO: 49 (pTP)

ATGGCCTTGAGCGTCAACGATTGCGCGCGCCTGACCGGCCAGAGCGTCCCGACCATG GAGC ACTTTTTGCCGCTGCGCAACATCTGGAACCGCGTCCGCGACTTTCCGCGCGCCTCCACCA C CGCCGCCGGCATCACCTGGATGTCCAGGTACATCTACGGATATCATCGCCTTATGTTGGA A GATCTCGCCCCCGGAGCCCCGGCCACCCTACGCTGGCCCCTCTACCGCCAGCCGCCGCCG C ACTTTTTGGTGGGATACCAGTACCTGGTGCGGACTTGCAACGACTACGTATTTGACTCGA G GGCTTACTCGCGTCTCAGGTACACCGAGCTCTCGCAGCCGGGTCACCAGACCGTTAACTG G TCCGTTATGGCCAACTGCACTTACACCATCAACACGGGCGCATACCACCGCTTTGTGGAC A TGGATGACTTCCAGTCTACCCTCACGCAGGTGCAGCAGGCCATATTAGCCGAGCGCGTTG

TCGCCGACCTAGCCCTGCTTCAGCCGATGAGGGGCTTCGGGGTCACACGCATGGGAG GAAG AGGGCGCCACCTACGGCCAAACTCCGCCGCCGCCGCAGCGATAGATGCAAGAGATGCAGG A CAAGAGGAAGGAGAAGAAGAAGTGCCGGTAGAAAGGCTCATGCAAGACTACTACAAAGAC C TGCGCCGATGTCAAAACGAAGCCTGGGGCATGGCCGACCGCCTGCGCATTCAGCAGGCCG G ACCCAAGGACATGGTGCTTCTGTCGACCATCCGCCGTCTCAAGACCGCCTACTTTAATTA C ATCATCAGCAGCACCTCCGCCAGAAACAACCCCGACCGCCGCCCGCTGCCGCCCGCCACG G TGCTCAGCCTACCTTGCGACTGTGACTGGTTAGACGCCTTTCTCGAGAGGTTTTCCGATC C GGTCGATGCGGACTCGCTCAGGTCCCTCGGCGGCGGAGTACCTACACAACAATTGTTGAG A TGCATCGTTAGCGCCGTATCCCTGCCGCATGGCAGCCCCCCGCCAACCCATAACCGGGAC A TGACGGGCGGCGTCTTCCAACTGCGCCCCCGCGAGAACGGCCGCGCCGTCACCGAGACCA T GCGCCGTCGCCGCGGGGAGATGATCGAGCGCTTTGTCGACCGCCTCCCGGTGCGCCGTCG T CGCCGCCGTGTCCCCCCTCCCCCACCGCCGCCAGAAGAAGAAGAAGGGGAGGCCCTTATG G AAGAGGAGATTGAAGAAGAAGAAGAGGCCCCTGTAGCCTTTGAGCGCGAGGTGCGCGACA C TGTCGCCGAGCTCATCCGTCTTCTGGAGGAGGAGTTAACCGTGTCGGCGCGCAACTCCCA G TTTTTCAACTTCGCCGTGGACTTCTACGAGGCCATGGAGCGCCTTGAGGCCTTGGGGGAT A TCAACGAATCCACGTTGCGACGCTGGGTTATGTACTTCTTCGTGGCAGAACACACCGCCA C CACCCTCAACTACCTCTTTCAGCGCCTGCGAAACTACGCCGTCTTCGCCCGGCACGTGGA G CTCAATCTCGCGCAGGTGGTCATGCGCGCCCGCGATGCCGAAGGGGGCGTGGTCTACAGC C GCGTCTGGAACGAGGGAGGCCTCAACGCCTTCTCGCAGCTCATGGCCCGCATTTCCAACG A CCTCGCCGCCACCGTGGAGCGAGCCGGACGCGGAGATCTCCAGGAGGAAGAGATCGAGCA G TTCATGGCCGAGATCGCCTATCAAGACAACTCAGGAGACGTGCAGGAGATTTTGCGCCAG G CCGCCGTCAACGACACCGAAATTGATTCTGTCGAACTCTCTTTCAGGCTCAAGCTCACCG G GCCCGTCGTCTTCACGCAGAGGCGCCAGATTCAGGAGATCAACCGCCGCGTCGTCGCGTT C GCCAGCAACCTACGCGCGCAGCACCAGCTCCTGCCCGCGCGCGGCGCCGACGTGCCCCTG C CCCCTCTCCCGGCGGGTCCGGAGCCCCCCCTACCTCCGGGGGCTCGCCCGCGTCACCGCT T AG