KR20070055860A - Methods of screening anticancer agent by using dnp63 promoter - Google Patents

Abstract

The present invention relates to a method for screening an anticancer agent using a promoter of DNp63, wherein the DNp63 promoter, a recombinant vector comprising the same, and the recombinant vector, which induce expression of a DNp63 protein in contact with a potential anticancer agent in epithelial cell-derived cancer cells It relates to a screening method and kit using.

DNp63 promoters, anticancer agents, screening methods

Description

Method of Screening Anticancer Agent by Using DNp63 Promoter

Figure 1 shows the location of the DNp63 promoter site cloned in the present invention.

2 shows the process by which ET-gene recombination is performed.

3 is a cleavage map of the vector pBACe3.6 plasmid used in the present invention.

4 is a cleavage map of the pGETrec vector used for ET-gene recombination.

5 is a part having IRES-NLS-GFP-Km used as a cassette.

6 is a cleavage map of the pEGRP-C1 vector into which a cassette is inserted.

7 is a cassette for ER-gene recombination obtained after PCR with a primer with a cancer sequence of 50 bp after cloning.

8 shows that the established recombinant vector expresses epithelial cancer cells specifically. ME180 cells, which are DNp63 overexpressing epithelial cancer cell lines, and HeLa cells, which are cancer cell lines that do not express DNp63 as a negative control, were identified.

9 shows that the established recombinant vector has a weak expression level before TGF-β treatment, but the expression of GFP is significantly regulated through the increase in the brightness of GFP after the treatment.

80% of human cancers are epithelial cell-derived cancers. Based on the idea that cancers may be derived from stem cells, they are specifically expressed in stem cells and cancer cells, and the expression of ΔNp63α is known to be inhibited during differentiation. Functionality can be very important. In addition, ΔNp63α has a function of inhibiting the function of p53 in the proliferation and death of cells, and functions as a gene for regulating cancer during overexpression. As a result, quantitative balance of p53 and ΔNp63α in stem cells promotes cell proliferation and differentiation. It is thought to control. Therefore, it is inferred that stability and protein position of ΔNp63α will play a very important role in functioning as a cancer gene.

DNp63 is a homologue of p53, a cancer-causing inhibitor, and is expressed as a protein having a function different from that of TAp63 due to a promoter (transcriptional regulatory region) inside the ORF of the TAp63. DNp63, which is expressed in this manner, does not have an amino-terminus transcriptional activity domain, unlike TAp63, and is specifically expressed in epithelial cancer cells as a cancer generating gene that functions as an antagonist of p53. Nuclear protein p63 is located on chromosome 3q and appears to have homology with p53. p53 protein is a cancer suppressor gene that contains a multifunctional DNA-binding protein that is important for regulating cell cycle and cell death. p63 exists in three isoforms. Each produces two groups of transcripts by two selective promoters. The first encodes a full-length protein with an N-terminal transcriptional active domain, such as p53. This can cause cell death. The second encodes a truncated protein and lacks the N-terminal transcriptional activity domain (ΔNp63). ΔNp63 inhibits p53 transcriptional activity by and / or full length of p53 in a dominant negative manner.

US patent application US20020094547A1 (differential diagnosis of cancer and other conditions based on expression of p63) The invention relates to a gene product of p63, a nucleic acid comprising this gene, mRNA and a cDNA comprising the gene. And the use of products of this gene in the treatment or diagnosis of certain diseases such as cancer. The present invention relates to kits in which such diagnostic and therapeutic methods are used. In the US patent application, a method that can be distinguished by measuring a gene or protein of p63 in differentiated lung cancer cells and undifferentiated lung cancer cells has been proposed. The absence of p63 suggests that it is an undifferentiated lung cancer cell.

In international patent application WO04048520A2 (name of invention: REDD1, A Transcriptional Target of p63 and p53, and method of use therefor), the common transcription associated with the regulation of p53-dependent DNA damage response called REDD1 and the differentiation of p63 mediated epithelial cells It describes the target.

European patent application EA0003326B1 (name of the invention: Method of cancer treating) is a method for treating human cancer, in which organic nonprotein compounds are contacted with human proteins of the p53 family and then stabilized, and the stabilized proteins are Disclosed is a method for treating cancer characterized by contact with one or more proteins participating in wild-type activity.

US patent application US6479285 (named p53 as a regulator of cell differentiation) provides a method of inhibiting the activity of p53 and screens these tissues as a screening tool to find substances that can overcome p53-related blocks in differentiation. It can be used. However, the expression level of DNp63 has not been used for screening of anticancer drugs.

The present inventors have found that the expression level of DNp63 can be used for the screening of anticancer agents and completed the present invention.

The present invention seeks to provide a method for screening anticancer agents using the DNp63 promoter.

The present invention relates to a DNp63 promoter characterized by having SEQ ID NO: 1 which induces expression of the DNp63 protein by contact of a potential anticancer agent in epithelial cell derived cancer cells.

The present invention relates to a recombinant vector for screening an anticancer agent comprising a reporter gene for confirming expression with the promoter.

More specifically, the reporter gene relates to a recombinant vector for screening an anticancer agent, characterized in that the green fluorescent protein (GFP).

The present invention relates to cancer cells derived from epithelial cells for screening anticancer agents transformed with the recombinant vector.

The present invention comprises the steps of transforming the recombinant vector into epithelial cell-derived cancer cells;

Contacting the potential anticancer substance with the cancer cell;

It relates to an anticancer substance screening method comprising the step of measuring the expression amount of the reporter in the cancer cells.

The present invention is epithelial-derived cancer cells transformed with the recombinant vector;

Means for contacting a potential anticancer substance with the cancer cell; And

It relates to an anticancer drug diagnostic kit comprising a means for measuring the expression amount of green fluorescent protein in the cancer cells.

In a first aspect, the present invention relates to a DNp63 promoter having SEQ ID NO: 1 which induces expression of the DNp63 protein by contact of a potential anticancer agent in epithelial cell-derived cancer cells.

Potential anticancer agents according to the present invention refer to substances effective for killing cancer cells.

In a second aspect, the present invention relates to a recombinant expression vector for screening an anticancer agent, comprising a promoter gene for confirming expression with the promoter.

The term vector, as used herein, refers to a nucleic acid molecule capable of binding and transferring another nucleic acid thereto. The term expression vector includes plasmids, cosmids or phages capable of synthesizing proteins encoded by each recombinant gene carried by the vector. Preferred vectors are vectors capable of self-replicating and expressing the nucleic acid to which they are bound.

In a third aspect, the present invention relates to epithelial cell-derived cancer cells transformed with the recombinant vector.

The term 'transformation' used in the present invention means that foreign DNA or RNA is absorbed into a cell and the genotype of the cell is changed.

Suitable epithelial cell derived cancer cells include, but are not limited to, HeLa cells, HaCAT, ZR-75-1, or ME180.

Transforming the recombinant vector into epithelial cell-derived cancer cells in a fourth aspect;

Contacting the potential anticancer substance with the cancer cell;

It relates to an anticancer substance screening method comprising the step of measuring the expression amount of the reporter in the cancer cells.

The method of confirming the expression of a promoter in cancer cells can be performed using a reporter gene. Reporter genes are not limited to specific genes. Any gene that expresses a product that can be easily measured can be used. Suitable reporter genes are well known to those skilled in the art. Examples of reporter genes include other enzyme detection systems such as CAT (chloramphenicol acetyl transferase), luciferase, beta-galactosidase; Bacterial luciferase, alkaline phosphatase and green fluorescent material (GFP) are included, but are not limited to these. Detection of reporter genes is well known to those skilled in the art. When a reporter gene is detected by its enzymatic activity, it generally comprises providing the enzyme with its appropriate substrate and detecting the reaction product (eg the light produced by luciferase). Detection can include simply detecting the presence or absence of the reporter gene product. Another method may include quantification of the expression level of the reporter gene product. The method of quantification can be absolute quantification or can be quantified compared to the expression level of the housekeeping gene. Such detection may be performed manually or may be performed automatically as in a high-throughput screening system.

High throughput test methods for the presence, absence or quantification of gene expression are well known to those skilled in the art. For example, US Pat. No. 5,559,410 describes a high throughput screening method for proteins and US Pat. No. 5,585,635 describes a high throughput screening method for nucleic acid binding. U.S. Patents 5,576,220 and 5,541,061 also describe high throughput screening methods for ligand / antibody binding.

In a fifth aspect, the present invention provides a method comprising cloning a ΔNp63α gene and a reporter gene capable of identifying the same into a vector;

Transforming the cloned vector into epithelial cell-derived cancer cells and expressing the cloned vector;

Contacting the latent substance with the cancer cell; And

The position of the ΔNp63α gene relates to a method for screening an anticancer agent comprising the step of confirming migration from the nucleus to the cytoplasm.

In a sixth aspect the present invention is epithelial-derived cancer cells transformed with the recombinant vector;

Means for contacting a potential anticancer substance with the cancer cell; And

It relates to an anticancer drug diagnostic kit comprising a means for measuring the expression amount of green fluorescent protein in the cancer cells.

Hereinafter, the present invention will be described in more detail with reference to Examples. However, the following examples are illustrative of the present invention, and the content of the present invention is not limited by the following examples.

The inventors of the present invention have a promoter (about 56Kb) stored in pBACe3.6 having about 150kb of p63 Mus musculus genomic DNA containing a promoter portion of DNp63 that is specifically expressed in epithelial cancer cells. , And in humans. DNp63 is expressed in vertebrates and fugu has the same genes and regulators as compared to humans. In addition, since it has a nucleotide sequence of 1/10 of the human genome, there is an advantage in finding an evolutionarily conserved nucleotide sequence through gene comparison. The recombinant vector was established by the ET-gene recombination technique using GFP (Green Fluorescence Protein) including the internal ribosomal entry site (IRES) behind the 56 Kb promoter.

ET-gene recombination is attached to 5'- and 3'-site of the DNA fragment to be inserted as shown in Figure 2, by attaching a homologous arm of about 50bp corresponding to 5 'and 3' of the insertion position, A new technology that inserts DNA fragments into the BAC plasmid site at the intended site by gene recombination of the same-arm arm, and is used when subcloning through existing restriction enzyme cleavage linkage of more than 100 kb is impossible.

In RET / ET recombination, the DNA molecule of interest is modified by homologous genetic recombination in Escherichia coli expressing a protein derived from Reda / Redb from a lambda phage or a phage derived from RecE / RecT from a Rac phage. RecE and Reda have 5 'to 3' exonuclease activity and RecT and Redb are DNA annealing proteins. Genetic recombination occurs through homologous moieties. The homology to gene parts can be arbitrarily determined, allowing accurate and specific exchange of genetic information between two DNA molecules.

Example 1 Preparation of Recombinant Vector

Vector pBACe3.6 was used. The sacBII gene was inserted as a positive selection marker. The sacBII gene obtained from Bacillus amyloliquefaciens was derived from Nat Sternberg's P1 vector. Toxicity of the sacBII gene is caused by the conversion of fructose derived from polysaccharides to polyfructose (leban). It is toxic to E. coli. Cloning vectors and recombinant clones do not carry the sacBII gene, making them resistant to sugar. Therefore, undesirable clones are susceptible to sugar and thus cannot form colonies in a medium containing sugar. (Ref. Fregen, E et al. (1999) A modular, positive selection bacterial artificial chromosome vector with multiple cloning site.Genomics 58: 250-253)

An insert was inserted into EcoRI of pBACe3.6, and the clone number containing the p63 genomic DNA sequence is 329J23 Escherichia coli. The sequence of the promoter is shown in SEQ ID NO: 1.

A cleavage map of the pGETrec plasmid used for ET-gene recombination is shown in FIG. 4. The pGETrec vector is a vector expressing RecE and RecT, which are enzymes for ET gene recombination, and overexpress the protein by the arabinose induction system. Induction was performed using IPTG (final concentration = 1 mM), and DH10B bacteria were used to make competent cells for electrophoresis by induction for 3 hours.

Next, a vector having IRES-NLS-GFP-Km, which was used as a cassette, was prepared. IRES-NLS-GFP was used in the pBS / KS vector (Emma Dormand 1999). A schematic diagram of the cassette portion used is shown in FIG. 5. The cassette was cut out with EcoRI, SalI and sub-cloned into the MCS (multiple cloning portion) of the pEGFP-C1 vector (Clontech). Information on the pEGFP-C1 vector used is shown in FIG. 6. After cloning the primers for ET-gene recombination after PCR with primers with 50 bp of cancer (forward: TGCCCTCTCTCCATCCCCTGCCATTCCCTCCAACACAGATTACCCGGGC (SEQ ID NO: 2), reverse: GCCCAGAAACCATATTGTTTTGTTAAATATTATTTGGTGATGTCTAGGA (SEQ ID NO: 3)) after cloning. 400 ng of the cassette obtained by the above method was induced by pGETrec and transformed into DH10B Escherichia coli, which produced the competent cells, by electroporation.

Example 2 Established Recombinant Vector Confirms Epithelial Cancer Cell Specific Expression

In our recombinant vector, IRES-GFP is inserted after DNp63 promoter. GFP (Excitation maximum = 488 nm; emission maximum = 507 nm) has the advantage that it can be easily identified under a microscope by emitting a green wavelength at a specific absorbance, and IRES regulates the expression of GFP specifically in the promoter of DNp63 upstream. .

It was confirmed that the established recombinant vector specifically expresses epithelial cancer cells in ME180 cells, a DNp63 overexpressing epithelial cancer cell line, and HeLa cells, a cancer cell line not expressing DNp63 as a negative control (see FIG. 8).

As can be seen in Figure 8, it was confirmed through the GFP that the expression level is high in the cancer cell line ME180 overexpressing DNp63. However, when HeLa cells do not express GFP, it was confirmed that recombinant vectors are specifically regulated in cell lines.

Example 3 Confirmation of Promoter Function of DNp63 Gene Available for Anticancer Screening

In addition, the promoter of DNp63 gene, which is specifically expressed in the cell, may be used for anticancer drug screening only when the expression level in the cell signal is controlled. In our laboratory, it was confirmed that the expression level of DNp63 is increased with respect to TGF-β signal. Based on this, it was confirmed in human mammary epithelial (HME) cells that the recombinant vector increased GFP brightness for TGF-β signal.

As can be seen from the results of FIG. 9, the established recombinant vector has a weak expression level before TGF-β treatment, but it shows that the expression of GFP is specifically controlled through the increase in the brightness of GFP after the treatment.

DNp63 is an indicator gene specifically expressed in epithelial cancer cells, and the recombinant vector according to the present invention, which has only a specific transcriptional regulatory region of this gene, expresses a fluorescent protein, and thus can be easily identified with the naked eye. Do. In addition, as can be seen from the above, the expression of the cell line-specific and signaling system-specific expression is controlled, suggesting that the expression level of DNp63, an index gene of epithelial cancer cells, may be a criterion for judging the action of anticancer drugs. do. In other words, substances that inhibit the expression of GFP, a fluorescent protein in epithelial cancer cells with recombinant vectors, may be useful as anticancer agents, and the test method is simpler and more cost-effective than those previously used for screening anticancer agents. It has little advantage and short time to check, so a large amount of anticancer substance can be used for screening in the future.

In addition, since DNp63 is strongly suspected as an indicator gene for epithelial cancer cell expressing stem cells, anti-cancer substances that specifically eliminate the expression of DNp63 prevent the cancer from recurring by inhibiting the growth of stem cells. Recombinant vectors that can be used to screen for breakthrough anticancer agents.

<110> Seoul National Univesity Industry Foundation <120> Methods of Screening Anticancer Agents By Using DNp63 Promoter <160> 3 <170> KopatentIn 1.71 <210> 1 <211> 56396 <212> DNA <213> Artificial Sequence <220> <223> Recombinat DNA <400> 1 cctcttcctg tgtgggcaag actagccaca aatcaaagga gatgactctg attggacaac 60 accattacag agagagcaaa tggagcccac tgggaaagga ttagctgggg ttttgtagat 120 tctggctctt tctcagcttt ctgcagtggg tagggacaga aggtggaaat gatttcttac 180 cttttgttgt ttgtatggtt tttttttttt cctgaggtgt tattcatgtt aaggctaaat 240 tagagagggt aatgtcacaa gggtttccaa ttcatagaga agcagacact ggacctgatt 300 ctgcccagat ccattccact gttgtacatg ttccatgcca acactcagga agtaaagcac 360 aaagaaacac acatgataca gaagctgtat tgtttttttc tttcccatgg tgttgctcat 420 gttgttagga tgctaggtct gttacttctt tattaaatgg tgaactcata ccagtgactt 480 ccatctctgg ctaggtcagg agtattactg ttaattttga aacagatcct gtaataagga 540 aaacactctg ataattccaa gcaaaagtga acctgtctta cagaagttgt gtgttcttgt 600 actcaaggga ttttttattc tgactcttgg ctacataaga actgaaaaag 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1500 gctttccaag gcttagtagc agactttctc gtttccatta taggttaatt gctaaatact 1560 ttcaaaagtc tgcacataaa ttactttccc catcaatata gtattttaat aagttgggaa 1620 ttcagccaat tcctttctca ctacacaaga aatacaactc tataatgggc atgaggaggc 1680 atgtcgaatt cttaaggaca gaaattgaaa aattcatcct atggattttc tgagttttga 1740 tatggccaag aaatggaatc gtgatgtttt ggtcttatta ttaacaaagg aaattaaagt 1800 gcagatgtta aattaggatt attaaatttt agattctgtg tgtcttttaa actagaatgt 1860 gtttcctaat tataaaattc tgaatattag ttctattggg atatgaatgg gggtaaatga 1920 aatgtctcaa aaaatcatat tttaactcta tttttcaagt gccttaatga accttgattc 1980 tgttgtttga tatattgctg tatttctcag atttgtatta ttttggatct gtgtaagcat 2040 gtctctatta tgtttgaggt atgaattcaa tattaacagt tacacattct cctcagtgat 2100 ggatgctggc caagcaagca tttgcattta tttattcttt atctttcatg ctaaattaga 2160 attttcttta aggaaactga ctggtaacta tctaaaatgc tatgtatttt taaatcctaa 2220 tggactcatc tcagatacat ataagaagtt ttcagctcta cattattaaa agactaatat 2280 caagatgtgt gcatgtatgt atgtgtgtat gtatatttat gtgtgtatat atttgtgttt 2340 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ttcacgtatc tatttttgtc tttgcataac ttagtggcaa ctctaagaat ctctgtttta 4920 cacctctgtc atccaccaag aattgacata gaagaaaatg tagaatggaa tatggaaact 4980 cttggcctct ttgcactgta ggcacacatt ctgcatcagc agacactgaa tgttacagca 5040 gaaaagagca ttgatttcac tttcaactac ctaagcattg aactccaaag caaaattatg 5100 ggcgagtttt gagtacaatt cttaacagct ccggtgctct tgcttagggg aaaactgtaa 5160 ttctcattgt gcattgctaa gaaaacgata gaactccagt cgctatccgt taccagaatg 5220 gggttttcaa ggtaaacagc acctatgctt ttaagcagag cagttagata gcctaaactc 5280 tcattcagaa tcttgaatct ttcggaattt ataaatgaca ctttaatttc tacttttccc 5340 cctttgtctc agcttgcaac tgcacttaca cacatgaatg tactcacaca gaatgtaatt 5400 tgaaccacgc ttactttata atattagata attaagtcag tacagctttt ggtatatatg 5460 ttgttttaag tcttcctctg ccatgtttta tgatttaagt atatataaag tatatacctt 5520 ccaaaaaacg tctaatttaa agtcactcac agaaattact ctgagtaact taaagcaggc 5580 tgaggagtta gtaagttaca cacatgccct ctccttgctt caaaaagttc tgatgtgtta 5640 ggcaagaagt aagcatttgt cgtttgctat gtgcccttgt ctcctggttc ctaagatgtg 5700 taatatcagc tgactaagcc ttgcaccaat gggtagaact tcctacaagg aaagtatcat 5760 tcattttctt ctcttcactt tcttggcttc cagaagacct ctacagatca ttcccactcc 5820 caccatctga tccctatcgc ttccctacaa cacctatcca cttgtcttgt catttaggaa 5880 accgattcaa tcagtgtagg tagatttggt taaaagcatt gggaaatggt caatgaatac 5940 gatgctatga ggttctccac cttttgttgc taaattatat catgggattt gtaatgaaaa 6000 caactggtgt tggatttgtc ttcaaaactg taaagagggt ccagtaacat ctacccataa 6060 acaggcctgt cctcagttgt atagaaaagt ctaataacag aagtctttac acaggagaat 6120 cgtggtgttt tgcttctttc agattcctta tgtgtataaa tatagagtca atcacttgag 6180 atttttttgt ggtcacttgt ctactttgct tataagctct ttaaatacag taaatagatt 6240 ctgctttaaa aataatggta attaatttat ctactaaaat aataaattta agaattttat 6300 atactgtaaa aagcacatat gttcctaagt catgataaca catatgaaca ctgcaatttt 6360 cttctactct tctttttaga aaaaaaaaaa cacattttga gtcatgtcat aattaattct 6420 tttccttttg ttgaaaatgt tttttgtaat atagaattct gactattctt tcctcctact 6480 tctccagttc ctccccacct cctctcccat gcagatccac cccatttctg catctcatta 6540 gaaaacaaac tggcttctaa aagataatta caataaaaaa atataacaaa agctaacata 6600 tcatatttga acaaaacaat cgaagcagag gaaagcagtc caaaagaagg cacagagacc 6660 tattcattta cacaccccaa aatctcataa aaacagtaaa tgattgcaaa ggacctgtaa 6720 ggtaaaaaga gagaagaaaa atatacaaat aaaatcatat taaaataaag aataacgcaa 6780 tgaaatttta caaagtaaaa aggaagtgtc ctgacatgac atgagacaag ctacatccag 6840 caatgccatt gactttattt ctcagtggcc atttattgct ggacaagaaa cctgcccttt 6900 agtttgttac tccagtggga ctccctagga ggaaactcaa ttttcatttg caagcggtta 6960 tcatttggag attgctttga gtgttaggtt agatatagaa gcacatgtgt cacatctcct 7020 gtcgaccata gaaccctatc tggtacagat ccttgcaggc ccaatgctta ttgccacagt 7080 ctctgtcaat ttaatatgtg tgttgatctt gttgattgag agagccttgt tttcttaatg 7140 acctctagat cttatacctt ctctgcccct cttctgtgag gttccttaag cccgaaagaa 7200 aagatttgat ggagatatcc catcaaaggg ctgagtattt caaggtctct cattttctgc 7260 ataatgtctg aaggtgagtc tctatttttc tttccatctg ctacaggaag aggcttctct 7320 gatgatggca gagcaagaca ccaatctatg agtattttta tgggataatt tgaagaatat 7380 tgactttaac tcttctttga aagcctggta gaatttttgt tagaagtata tggtcttagc 7440 catggtcttt ggttttgttc ttgtgtttct tatcgttgtt ttttagttgg ttggttttgg 7500 ttcttagact cttacagtat aggttatatg tctcttaaaa ttgcttatct agtggattta 7560 aactttacta tgtagtatgt attgagaaaa ttatgtgttt cttttagatt ttccacttgg 7620 tggagtacaa aatttttaaa gcatgtcctt atgattttct ggattttctc agtgtctatt 7680 atatcccctt tttatttcta cttttgttat tttaaatatt cttcctctct acctttaaat 7740 tactttggat tagggttact caatcttact gatttttctc aaagtatagt tctttgtttc 7800 tattttatta ttttcatctc tgattttatt tctttatgtt tactcatttt gtatgttatt 7860 tcttcttttt gttctagagc tttcaggggt gcatttaaat tgctagtttg agatccctcc 7920 agattttttt ttgtgtgtgt ggtaattatt tttattttta atgtaacgca gtattgtaga 7980 acttcccacc tagagtagtc ttcattgagt catataaatt ttgatatgtt gtacattaat 8040 tttcattcaa ttttaggaag tctttcttaa tttctgtctt gaaccttgtt ttatttagta 8100 gtgatttgtt caatttccaa gagtttataa ggtttctgtt gttgatatcc atttttaatc 8160 catcatggcc agatagaatg taccggttag ctgtttcaat tttcttgtat ctgttgagat 8220 ttactttgtg tctgagtatg tggtcagttt tggaataagt tccataaggt gctgagaagt 8280 tacattcttt tgtgtttgga taaaatgttc tgtaaatatc cactaaccca tttaacttat 8340 aacattgatt tgcttcagca tgcttctgtt tagtttttgt ctgattgacc agtctattgg 8400 caagaataga ctattgaagt ctcccactat cagtgtatgc cagtcattat gtgatttaaa 8460 ctgtagagtg tttctaatat gaacttgtat gcccttctgt ttggtgttca tatgtttaga 8520 attccaatat tctcttggtg gattttttat ttgatgagta tttactgttc tttcctatct 8580 tctgataagt gtttgcttga agtctatttt gttagttatt aaaatggcta taccagtttg 8640 cttcttaagt ccatttgctt gaaacacatt tatccatgct tttaccacaa tgtgatatct 8700 gtcgttgatg ttaaggtgtg tttcttgact acagcagaag gatggatcat gttttccatc 8760 catttggtta gtctctttct tttttattgt agcaattgag gctgttgata ttgagaggta 8820 cctcctcctt taggttaggg aaattttgtt ctatgaaatt ttttcaaaaa ttttttcagt 8880 gcctttgatc tgtgtttctt ctttccctat tcctattatt cttagatttt ttttcacagt 8940 gtcagacttt ctggataatt tatgacagat tttttttttt gatttagtat attctttgac 9000 tgaagtatcc atttcttcta tcatgccttc aatgcctgtg atcctctctt tcatattttg 9060 tgttttgttg gtgagactga ttgatatgcc tattcaagtt ccttggttat taatttccag 9120 acttccctca ttttgcgttt ttcttgattc aatttctgcc ttcagatctt gctcagcatt 9180 ctgcagttgt gtgtgctatt ggtgttatca ctgaattttt aaaggggttt atttatttca 9240 tcattaggag cctttattgt attcataaag gcaatttaag gagtttttct tatgctttga 9300 ctgtttttca attctcagga cctactgtgg tggggttcct aggctctagt ggaaacacat 9360 tgtcctggat gttattcatt atatgtttat gctggagtct agacatctag gtttgcaaga 9420 ttgtaattct tgctgatatc tggtgttgtt tttcttgagt ggctattttg gctccttagt 9480 ttctgttgcc ctgattggtt cttgggagag tgttatggct gtgtgctgcc tggttggaaa 9540 ttcttctggt attctggtag acatggtcac tatgggttcc agatagaatg tgctcctgct 9600 tccctatctg gagagtcata aacacatttt ataaaatctt ctattatatt tctgttatag 9660 atcttattta cttttcctcg tgtgcacgtg tgcacacaca cacacacaca cacacacaca 9720 attgctataa tacagattgt tcagatttac cacatttcaa cttttttgtt ggtagaattt 9780 ttttagaaaa tatttagatg tggatattct cttatgatgg atatttaaat gcatagttac 9840 tagataaaat tgtatacaca atgggcttgt ttccatgatt ttcttctttt attatttttg 9900 cttcctgttt acatttctgt taactacgca ggactgctta caaactggac atcattttgg 9960 tgatacagta tcttctaagg aaaatgcaaa tatttgtagg agtcgcaagt gtccagtgat 10020 ttgcacatta tactgaaatg tctcctttgg tggcatcttt cttttcggcc aagtttatct 10080 gtaggattca taaggataga cattttggct gaaaagaagc aagtcctctc agagactgga 10140 gcagttaatc aatggatggg caaactgtct gtgataggga cagtatggaa aagccatggc 10200 aaagatagta tgtatggtgt ttagcattca tcctgggcac aggaatggct atgtcctttt 10260 ctccttttcc tccagcactt cttaactttc ctatcaaagc tctagtagtt cactcagcct 10320 ggtgggctgt attctgtgaa gataattaag acatggcagc aagggaacat ttcactagac 10380 aaaaacgccc cagcaattcc tatggagtct gcgtgtaatt acctatgctg cttatgggga 10440 cgctcactct acacttagtg tagacggagt tcagacgtct ccgacagcag actgcttttc 10500 tcttttcttc tttgtatggc ctagccaata ggaagacatt actttgttca agagtgccaa 10560 gggagcgact ttaccttaaa cacacatatg catttcaacc ttgaacaaac aggctgctta 10620 ataaaataag ggcaagggtt ttcttttctt ttctttcttc tctagaaatt cacaaatatc 10680 acttgacagc tgacagctct tcccttacaa aagaagctgt ttgctttttg ctttggtgtt 10740 tgggtaaact gcagcccaca ctggcagaga atgtattgcc taagggaagg tgtttgcagt 10800 ccctgtgttt aatctgaaaa gaaacccttt tccttctctc cttccctctc cttctgcacg 10860 gggagagttc gaaatgatag cccgagggga atagtttcct tcacacctgt ctgtggtgta 10920 acctcagcaa agttacttaa gacgccgtgc tcagtgtgtc cagattcaca atgaagttga 10980 aaaggacacc ttctgcacgg ggagagttcg aaatgatagc ccgaggggaa tagtttcctt 11040 cacacctgtc tgtggtgtaa cctcagcaaa gttacttaag acgccgtgct cagtgtgtcc 11100 agattcacaa tgaagttgaa aaggacagat aaacagacag ggatttcagc agacgagggg 11160 agctgatggt ggccttgcat cttcaaactt tagcaggttg acatcctagc atgctgactc 11220 gcaaagaaag aatacaggct ctccttcagc caggaaatat agttcaatct gaacagctat 11280 attaaactct taagagatta agggaacttg ggaaatgctc tagtgtctgg tacactcttc 11340 tacattgact agacagctaa gagccaagtg acccttggga catttctgat aagtatgagc 11400 ttggagtgac cccagctttc tgagtttcta gatctggtcc cttggctgct gggagaagca 11460 atctaaaggg ttcagcctct tgaggcttgt cattgacaag ttcagtcctc ttagaaaaag 11520 tacaaaatga ttttgaggct ctgtcttcca ggcagcagaa ggaagatgct gatattggct 11580 actcgcagtg gacaaacaat tttgaaatgg caattttgca ccaaaaagtg gttaaagcag 11640 tacttttcat ggtcagcagt gggagcattt atatggttaa aatgggatct ctttaaaaac 11700 tgaattttta atcccaagtg cagcaattat taatgaagaa agaaaataat agaaatttgt 11760 atattcttcc ttttgaaaac caggtgttac ttgctgtgaa atgggacttg accactcttt 11820 cctccttaaa tgtagacagg gttgagttgt gggattttta gctttgtttg cattcttttg 11880 ccctttaaaa aaacaaaaca aaacaaaaca aaaacaacaa aaaaacaaaa acatggccaa 11940 agtttcaaaa tagacagatt tcctctgaaa atcaatatag tgttttgtat gttcaggtcc 12000 caaagaactc actagaaaac acacatttct tttgttcact actttgtaca ctcctccctt 12060 gtcattctgg ctttgcagta gtcttttcca gtggagggat taggagcatg aactttagtg 12120 gctcgacaca tagatacagc tgggtttcag ccttagtgta tcagggaagt tagttctgaa 12180 tagacccaag acatggttta attctcaaag catcctctga ggaccaacag catcaagatt 12240 actcagaacc ttaagagctg gggattcttg ggtatcactc cagagacaga gtcagaaact 12300 aatgggaaaa tgacactgtc tgtctttcca cacaccccat gcttacttat gacagacaaa 12360 attcattctg tatgtgtgtg tgtgtgtgtg tgtgtgtgtg tgtgtgtgtg tgtgaccaga 12420 taaagataca aaactgcgaa gacagagaag aaacttctag agtggtgtct actctaaagt 12 480 gggcatttct gactatgact catattaaaa gatgtacaaa ggtttactac attttgaatt 12540 tagaaaatta agagtaaatc caggcatggt gcttagggcc catatgtgca gaagcagcta 12600 tgtgggaggg ggagacatga gtatcacttg aacttttgag tttgagacta gcctgagcac 12660 tgaaggaaga ccccatatca aaaagataaa ggctaagtgt aactgttgat aaaatatata 12720 cactagattg acctacatat gttttgtcag aaagaagtag atgaattata ttaccttcaa 12780 atttattttt tttaattatt atgtttttaa atttttcata cagtgtattt tggttatatt 12840 ctctctttct gccaccagct tttatttcct taatagtata aatggttcat tcaaatgtct 12900 tccctgggag agacttaaaa tgtcaatgca tgttcttacc tgaacaagtg tgcactgata 12960 gtctatagaa ttcatgactc tattagaggt actcagaaaa aatatttgct gattgaataa 13020 tgagaaatga atagaaacga tgaaaatatg tgcttcccct agagtaataa ttcagtcata 13080 tacatggaca gccgaggttc cagtgacaat cttcacaagg tactgtaagt gaagagtgtt 13140 tccgggcagt gagcatttta gtggtctggt ttcaggctga tacctgtagc tatgcttagt 13200 ctgcaaacta acggaataaa tgggattaaa aaaaatcttc ttccaaggaa cttccaagtc 13260 ccaagggaag ggattcctac aaacaactgt cattgggatg gaaagggctc agtactgtga 13320 gggactccac ctgagacacc agcaggaatt ctgacgagct tgtttctgtt ggaaagctga 13380 agaaataaga agactatcta aaagaagaaa agaaaaaaag agtattcctg gagacaggaa 13440 tgactcaaga ccaggatccc aggatttagc ttaaatacat caagcactga atgcaaggtg 13500 atgaatagca gtgcctacaa agactggaaa gctacatgag tcacctagtg actcagatga 13560 caatttggag cctttcctgg aaggggaggg atatagctca gttggtagga cccttgcata 13620 gaaccacagc tctgagttca agagtaagca cttaataaag caggcataac tatctgtgcc 13680 tagaatgtaa atgctcagga ggtagaactc agagcaccag gcactcaaaa gccactctca 13740 cttacatagc cagtttgagg aaaatatgaa gtccttggga ccctgtgtcc aaaaccaatt 13800 aactaaaaat ccccaaagaa cacaaaacag aaaagcagtt tactggaaac tgaaacagag 13860 aacatactgg agggccatcc atgtaaagcc ctgcttaagt acatttgaga atcaatgaaa 13920 ttcacccaaa aatctacaag caaggaaaag aatgtgacaa tggacaaatg gcagaaacag 13980 agtcagtata acaaaagagt tatgcctgga agctgtgtcc gtgctgagct ggacattagc 14040 tagacgaggg cagggagata catggagact gcgcatgtct gtggtctctg tgggcctgcg 14100 catgtctgtg gtctctgtgg gcctgccctc tctatggctc atcgtgaaga agagccggtg 14160 ttggggccaa tgattcagtc ggccttctga attagtccct gatcatcttg cccatattca 14220 ttgagaatag actcctcagg tagcaacagg gacaaaaact cagagttctc tttcttctct 14280 tgctttcact atcatgagag gaacaactgt gtacctcact aactattaca aaaagaacca 14340 gggtgctagg aatgaggggt aaaacaaagc tatgaaggac cattggctgt attataattg 14400 attagaaggg tcacagagac ctctccaggg caaaagaaaa acagtagatg tgtgtgacat 14460 tcacaccttc cgtatgctgt gtacacacct cctagagaat tgttctagac cctccactcc 14520 cttgatgctc cacttccctt gaggactccc ggtgcctact ggaagtagcc tgcctgcaac 14580 tccatgagtt tagttgtctc ctcttttgcc tgttaaactt attctttgtg tttagaacag 14640 atgtgtggtt cttttctgta ttaaaaatca aaacagcaac actaacaaaa gggaacaggt 14700 ccagctcctt tgcacttact cacggtcctg ccaagaaggt gagctctctt aatggatatt 14760 acttaagtca tttcttgcca caccttctta aagcagggaa aaatgagaag gtatttttca 14820 tgtgagactg ttgtgcctgt gtgccgcagg agagcgaaac agaaactata ttataaataa 14880 aatcgtgatt ttttttcctc ttcaactttg ccgcttgctt ccctacaaac cagagctgga 14940 tggccctgta aaatgtgggt tggtaaagtg acctcttcct tagatgtctg ggcggggtag 15000 cccattactt tcggatagat ggagcttaac tggggtgatc cggtgtgagt gatggctaca 15060 ctaggtgaaa gggatgagag gaaggcatct tagctgctga gttaaagaca cgcagccagc 15120 tccctatttg accatgccat tagaaacaga gacaactcgg atgcttgaaa ctgaaccaat 15180 agggaaaaac cgagggaggg tttgagaagc aaagtgatcc acttcatgag taactgataa 15240 aggaaccaag tagctcaata tgccatctcc gtttcctcaa aataaaggat acatcacatg 15300 caagattgag ctcttgggca gtcacctgcc atgagaaggt tttcagtttg agggtcgata 15360 atataaagca tgcttaaaag tatataatcc tccgcagcag tcaaatttag gtaggtaact 15420 gtggcctggg agttgtgagt cttggtctcc accctgctga tactgatggt tgtctgttga 15480 acacccatca cttctctctc gggatttagc ttccttaggg gtaagtaaga tcacaggttc 15540 cagctgcgtg acactccttt ctctcaagct tggcaatgac tacatttgcc agtctttgct 15600 tccaatttct gtctgactgg gttacctcta tcgaggtagt atgggcatgg cagaacctag 15660 atgaaccatt gctaaaacaa accctcttct atagaacacc cgcatggcct aaaagtctag 15720 agatcttgga ataacatctc tcttattatt tatttttctg gtggggggtg tttcaaaaac 15780 ctaaaacaaa agtcactttt tttctctctc tgagaaaatg cctggctccc gtctgccttc 15840 tgcaagggta tggtgggctg cagccattgc cttagtaatg attagtcata aagtgagtcc 15900 tgtctggagt gagagaagag gtaggtacct tccgtggctc tccactccct cactgaagct 15960 gctctatctc cctggccagc cccaggcagt gttccttcca aacaaggacc tgtctaacca 16020 gttcattgga atgtcattcc acagactatc tcctcattca gatttcttct gaaattgaaa 16080 cactctaaag acataaatca cgttgctgtt ttaagtagta aatgttgcac acagcagtct 16 140 tccaccattg cgttcctttt gagggcacag atttatccac aaaaggaaag aacaaaggga 16200 atgtgactaa gccctgggct gccttcttct ggtcagagac aacttctttt ttgctaggtc 16260 tgagtgtgta ctaggggtga cagggattaa ctcttcttga tgtaatcttt ccccctattg 16320 catgcctcgc tctgtccttc ctcctccagt ctacggctgg ctttatgaat atatttactg 16380 tgtgttttct tcgctggctg gtgctctggg gtcagcaaat tatacagtgt gaagcaaaag 16440 ctctaaatta cagtcatcat acaccaaacc atggaacagt atgtaaaaat gttttactct 16500 gataaacatc atgcctataa actccatgct tcaaaactca ccttcagtga cagatggcat 16560 ttgaagccat agctgaagga ttgctttgtt tttctcccct ttttattatc tgactggttt 16620 ctttatttga ttctacaaag aataaagtaa taaaagaaaa atatcatctt gagcagtact 16680 ggctgagatc atttttaaaa tatatatata tatatatata tatatatata tatatatata 16740 tatatatttg agtaatatat aattgtgatt ttataccaga cctccctact ctggggcatc 16800 tagtctctca agggttaggt gtatcttctt gcactgaggc cagagcaggc agtcctctgc 16860 tgcatgtgtc tgggaaggag ggtggtagtg gtggggtcat atcagctact gcatggtgct 16920 tggatggtgg ctcagtgtct gggagatctc aggaatccag gttagttgag actgttggtc 16980 ttcctatggg gtcgctctcc tcctcagctt caaggcaaaa tcattttctt atcctgatta 17040 catgtagttt ttaacaaagt tgggatggtt tgtgtttgta tattcagtga agggggattt 17100 gggttgggaa tcttgcaggg gacccaggtt cagttcctag tacccatgtg atgattcata 17160 accacctata actctatttc taaggaattc aatctcccat tcataggtcc caagcatata 17220 cagtacacat gcatatatgc aaggaaaaca cttatacact tataataaaa tgaatcatac 17280 atgttctttt ctagaagggg aatgttcatt tcttggtttg tgaagtagaa atgatagttc 17340 agtcttgtat aagctgaatt gagtgattgt tcctactcaa acctaaacat ggacaaacta 17400 aggcattttc tttgccagat tttgcttttc aaaatatctt cagagcctct tgagttgctc 17460 tgattctgtt ttggtcctac atatctcttg gtgcagagtc ctgaagccaa ctttacccac 17520 caagaagatc agctcatggc taacaaatca gacatattag tgtcatagat tataagttct 17580 gactaaaggg ccctgaaaag aagcctttaa tggctgacct gcaaagcatc tttagatata 17640 agcatccttg aaagcagact gtggtgcatg gggtaagctg cagcatccca tgttctgatc 17700 ataaaacctc taagcattta actgtgtaag ctgtgagccc agtaaactga ctcatgtcac 17760 taacccactc tgattttgct ttatgaataa aaaattgata ttcaaatcta gatgaaatgt 17820 tttctaaata attatatgaa aatgtaaaaa tacatataga tgttgatata tttagtgaat 17880 tacatagtat gtcaatatta aatattgatt ttaagaatta agtagattga gctctgtgat 17940 gaattaccct gggtatcata gtaactaact ttgagtttta ggatattact ctcctttttg 18000 gtgtgtgagc atatgtggtc atacacatgc cgacagcatt tatgaaagaa agtcatgtaa 18060 caaattgcag gagtcaatcc tttccttctg ccacatgtgc ttggggattg gactcagaag 18120 tacaggtttg tttacagaga tgaatggggg aattctgttg taaattcagc ccaaaagcta 18180 gttagtgtgg cttctggaga cccgtctagt cctggttttc cacttctaag tcatatgaca 18240 taagacaaat tatgtcatca cccaaagtgt cttcctcatg tgtaaaatag gatcataatg 18300 ctccatcaga acaagtatga aaatgctaag agttgtcctt aaataagaag tgtctaacaa 18360 atgttctctg tttttatcct gtggctatgt gggtatcatg tatgccttta tattacctgc 18420 ataggagatt gtgtgtcctc gagtgtctga atgcagaggt cagaggaaga catagagtat 18480 ttatttattg ttctgcacct tattgcattg aaacagagtt tcttgctggc taaacctggc 18540 cttgcttagc taggctagcc aatgagctag taggatctac ctgaccccac ttctcaatgc 18600 tgggatgaca ggcaagtgca gtcatgcctg gctttgtttg tgggtgctag agatttgaac 18660 ccatgtcctc ctgcttgcac agcacatgcc gtcactcgct gagccagctc tccacctttg 18720 cagatatgta tttttaaaag tatctggtgt tactacttta ataagttcta ttaccttcca 18780 aatctttagt tcagtataat gatcaagttg aataacagta tagaaagtta tttttggcta 18840 aaaggaaaga atttttcctt aagtttaatg ctaattagtc tgtttgagaa tattggattt 18900 tagaagtcat ttatacacat ctgggtgtga ttgatttgtg agaaggcaga gccctaccat 18960 caatttggag attgtgggcc ccaggaatgt aagggcttca ttgtgcttgt ttttcttggt 19020 cttgattgag aaagttactt caaaaaatta ttctttggcc aggagttggt agagtagtca 19080 ttaatcccag gactttagag gcagaggcag tcagatctct tagttcgagg acaggctggt 19140 ctacagaaca agttccagga cagccagggc cacacacaaa gaaaccctgt cttgaaaaac 19200 taaaaatact aatactaatt aataataaaa tgctttggcc ataattaacc caatagataa 19260 cactaatctt ggctttgatt aataacatgg ttatatggtt atagaaaata tgcatgtgta 19320 ggtagtttgt aagcactgca aaagcttcat caaatgaatg caacttttat atggctatgc 19380 acatttaaac ttcaaaaggg tctctaagag gctaactcag gcacttacat tgcttcaaag 19440 tctctttggg ccttaaatca gtgcaaacat attatgaaca taaatcgtcc ttattttaaa 19500 gttacttttt tccctgataa cattacctag tttgattact cagtttggtg gaaagcattt 19560 tttacaggat gaaaatttgt ccccattgat ggtatcccag tgatgaatca cagattgatt 19620 cacaatttgc agcagattgc tcaaagctcc agaacacaga aaaattacaa agcctggtac 19680 ttggcagtgc ttggcaaatg tctgatgagt ggttagggtt agagggctca ttgctaccaa 19740 aagttgttaa cttgttcagt aaagaggtac acctcaaata ttggtgatgt ctcataatgc 19800 ttggagtttt ttctactgtt ccattttgtt cctgattcct accactgagg cctgaactca 19860 ggacttcaca catcagaaag catgcgatat tctgctgctg actgtactcc tcctacccca 19920 ggttttccta atataacttt taatgagcat gtgtgacttc aatgatagtt tgtgtccact 19980 ttggtggatg ttatgccctc cacatatgct agctcttgct tttctcttca gttggagtgg 20040 gtagacttat ttaaaatgct tcttggacag ctattgaacc attcgtaata taaccaagca 20100 gcagaagggt gggtatctga gtgcttatca aaaggcatta tgcctagaag gctgttcttt 20160 tgttcttttt gattttcctt ttttaagaat acttttcttc aaatttatgc aaattttaag 20220 tgtccagtcc aagtcatcat tgccacagat tgttaggcaa gacgaaaagt ttaatgttgc 20280 aagttttttt cttgaaattg tgagtcactt ccactgtaca aattatgtaa gatgtcagaa 20340 gttttcattg gaataaactg aaattatttg cagtaagagt tttaagtgag atgtggtttt 20400 aaaaacaaag aaatatttca tgtttttcta acactatgta ttttaaattt ttattgagtg 20460 tgtgtgtgtg tgtgtgtgtg tgtgtgtatg ttgccatatt tgatatatgt ccactctaag 20520 ggcatagtaa ctatttctcc tcctttcttc ctcttcctct tcctcttcct cttcctcctc 20580 cccctcctcc tcctcctcct ccccctcttc ctcttcctct tcctccttct ttactgggca 20640 tcaaaaccta gggcttaaag catgatagat taatagtcga caactaagtc atattctcag 20700 ccatgttttt cgctatttat tttgaggcag aatctgaata aattatccat ttggattcat 20760 gcttcctcca gttccgcttt tttttttttt tttggtacta cactcatata ttaccaagcc 20820 agaactacct gaagtttttg ttcaattaaa tgttggaaaa gccacttaac tccatgcagc 20880 atatatttta gtattcatga ttaaatgaga actactcata gtattttgaa ccagtgctac 20940 ttgtggaaat atgggtgttg ttttggagtc cccaacttta aaaaattaag atttcaaaat 21000 acaatgtcat agtatattac atagtagcaa tgttaatgat caaacagaga aagaaagcag 21060 ggcagaagtc ttttgagatc actgggttgg tcttaaaact ttcaccattg taattactga 21120 tctgactgct ttttctttta taacagtaca tatttatata aaactccttg gtagaagacc 21180 agtatgacca agaactgcta aaggtttctt tggctgatct ctcacttatc tgcaaaatcc 21240 ttgcccatgg gcgaaaggtc tagacattgt ctgtgctgtg aatcaggtca gctcccaaca 21300 acatccggga agttggtgaa ctgcttaact tctttgatgg ataattcccc atttaacgtt 21360 tgtctgcctg cctgttgttt tagtgggatg atcatcctca gtaggactga gagcacatca 21420 gaaacccagt ttgcttgagt gtgatagtga cagatgttgc tcatgtttgc atgtcaaatc 21480 ataagggttt ggaagcattc ctttgatgac agttaagtaa acaaactatg taataataag 21540 tctaggaatt cattgagata ttcagctaat ttacttctgg tctgtgaccc aaattttagc 21600 cttccaagca gagcacctat tttgaattta ctggaaaacc aggtcacata agctcaccct 21660 ctctctcagg atgacagggc caggatggaa ggggaagatg ggctggcatg tgaacttttt 21720 actaataaag acacagatgc acagtaaagg aagggtgcag cccaagagta tacagccaac 21780 cgatgaatga gccagccaga tgaccaggtc tctgaatgta gggtctgtcc tttaaaacca 21840 tgcatctgtg ttttatttct taaagctaac cctccctcag caataatatg aatatcatac 21900 taccagtcat tttgtaagac cttccctctc agatatttag tgtttattca atgctaaatt 21960 tgatgcctag actgccgtgc ttcatgacaa agtgcaatga atctctgctt catttccaag 22020 acttgggctg taatagccga gtatatatat attatatata tatatataaa atagccgagc 22080 atatatatat gtctatagcc gatatatata tatatatata tatatatata tatatatata 22140 tatctccatc catccttccc cagccttggt ggtaaaatga tctagttttt tacaagtctg 22200 ccctttcaag aaggctaagc aggacatcca atcctccctt tgtagtaaga caggatgcca 22260 gagacatgac tgttactgca gacagaagtg ggcttccagg gaagaataag cagagacgtg 22320 ggtaacgagg agatagtagt ttgggtgtgc acttgcagtc tcgctgagca gctaaagctt 22380 gctgtatctg aaagcatcaa ggcccctcac atcacggaaa agcttcacct ctgctcatac 22440 tcaactcctg ctctcctgct ttttaaatga ggacaagatg ttccaaaaac taccagcagt 22500 gatatttttt tttttctttt tctgggaagc tgagtcaaag taagatgaag caatacctct 22560 gaaagttatc ttgatcttga tgtaatgttt ttctatatgc actttcctcc acaatgtgta 22620 actcggggga aaaaatcaag caaacaaaaa ctctcagtgt tagcaagtga ggcatccttc 22680 ctgtatgtta attaatcccc tcttgttgtg tcagaatcat tctctctaag caattctcat 22740 tcttgcattg atttattttt tcactcctcc aaattcttcc ttgggaatct tattttaggt 22800 gagtctttag acagtaaatg tgtcagacag cttcaagcta ctgtggctgc aagaagtcat 22860 gacgagaagc tgtgttagca gggttgacgg acctcattag agatgccaga gcatcttaat 22920 tttgtacaca tcttggaaat tcagacgatc tgatacatca ccaaaccaac aattatttcc 22980 ttataggtag actaggactc acaaatcaga ggtcaattcc caggagaact ggagaaccca 23040 gccagaccca aatgttatta ggtcatttgg taagtttcct ctttatttca caggggagaa 23100 tgattttctg gaggctaaga cattgaacac taagtgacac tgacattaaa gacactgctt 23160 acaactttat atgccccagt acaggggaat gccagggcca aaaagtggga gtgggtgggt 23220 aggggagtgt gggggggact tttgggatag cattggaaat gtaaatgagg aaaataccta 23280 attaaaaaac actgcttact tatcatgtcc atttattgaa ttttgtttgt ttgttttgct 23340 agctctggcg agtgagtgtg tccgtgtgag tgtgtctgta tctgtgtaat tatagaactc 23400 tttgggttag agacgatctc aaaggtcacc agatttaacc tccccagcat cctggccttt 23460 aactctgtaa ttactaaata gaagcttctg ccttctaatt ctcttagagg gaagcaaggg 23520 gggaaaaatg tcatccggtt cattctctga tcacaggaaa aatgtcaagc tggggagagg 23580 tttgttggtt ccacaagtgt gaagatctga acttgatccc cagtacccac ctacaaaact 23640 ggcggtggta gcatgtgcta gagatctgtg ctgggagcct aaagacagga cagccttcag 23700 gcctcaccag atagccagtg tagcctgcct ggtgagccac aggccagtgg gagccacttt 23760 ctcaaataga aagtgtgttt agcctaagag tgaatgacat ccaatgatgt cctctagtgt 23820 acacatacat atgcgcacgt gtatacatgc attatattca acatacatga atatgcatac 23880 acatgcacat acagagaaaa gaaaatacat cactaagtag aaataaacaa gcaaataaca 23940 aaataaaaac atctcatatt tgcctagatg ctcagatttt gtttaaagca aactgttgac 24000 ttttaataaa tattttcctt aaaacctaaa cttcagaggc aaggctatac agctcaggta 24060 cagagcttgt gagccactga gcctggtcct agacccgcaa attctaaaat aatcaaccaa 24120 ccaacccccg ctcaaagaaa aacaaacaaa aaaccccaac aaataaagca cataacttca 24180 tacttgacag gatatttaat aattataaat actagataag agtgagtctt caggtcatca 24240 tttattgtag ccaaattcac tgttttgggt ggggggcaat aagttctctt acaacccagg 24300 cttgtcacaa acatgttgtg tagctgagga tgacctgtag tttctgagca cccccactgc 24360 tggaattgca acatgcccca ccatatctct tttaggcagt gctgggtatc aaactcaggg 24420 acttgtgcat actaggcagt cactctgcca cttgagctat agcttcagcc cccacgttct 24 480 gtcttgtggc aattgctcac aagtgagata aaagaatata tgaaggaaat ggtggctggt 24540 ttgcactggg gacaagcctg caataaggat gttataaagc ctatgcattc ctgtttggga 24600 aacttcaata tatgattggg aattctaggc ttgtctgttt taatttctag tttagaagtg 24660 gtaaaattat ccccttggca acacccagat ttatgctgta agtgaggtga cttaggtggt 24720 ggtatcctct tttcatacat gagagtacaa acttcccact atcacagatc ttacagattt 24780 gaaggaagct ctttaactct agcccataat agatgtgttt caaatacaga attgggtaca 24840 gagtcctcat gtgccaccct gttcctctac ttgctttctg tcattttgtc ttttatttca 24900 tagtgctcct tgagtctaat ttttttcttt tctctcattt tattctttga aaagaatgtt 24960 attctctgat aactccatgc atgaattcag gctcctccat attcttctct cgacttcatg 25020 gcttttccct ctttgtccct catttcttct taaattaaat ggctttcaac atgcttgggc 25080 actgttatac ctctttgtct cttggcaggc tcaagtcttt gttgtttaat tctatctaat 25140 tctccatttc ttaattccct catgtcttgt gccttttata agccccatgc atagaacaaa 25200 caaaaaaatg tttcatacaa gctaaacaaa gctgtcttgt acattagtat acttaataga 25260 aacctgtcct ggacattaaa ccttaataaa tattgacagt agcatccaaa gcaggtgatt 25320 ggatgtatga caaggaactg tggtagatac tatggaaaat atgtagaatc ccataaatga 25380 aaatgcttgt gcttcttata gttgatgtca cacacaatgt gattcttcag atatcatatt 25440 cttgggatat gatactcaaa cagaccctgt gacaccagca cacagttaca aacatcaaga 25500 ccatcccttt ggtcttcgct ttgcactgtt cacctggaag tgcaatcaat agctcagatg 25560 tgtctacagt cctcattcat gtgacatctt ctagttcctg ccttacagaa atttggggtc 25620 actgtaatca tcactatctg ccattttttt tcatctttcc cctcatcttt tgcctttgga 25680 attttacagt tcctctgaga aacgatgtaa gaatccttcc atggcttgcc attcttttca 25740 gaaaaaaggg aggatagctt gggtactgag ctatcatcat aactctatac gtttagagtc 25800 ccagggaata ttggtaaaca gtgttggtga atgggcactt cattgactac actaacagct 25860 cattactcct gcatccacag atgagtactg acgaagaaat gggtccttgt ttagatttta 25920 aattttacca ggagaataaa ctcttcccta ctctctactg gagtaccctc ttccgaggcc 25980 acagatatgc cagtggcctg gtttaaaagt atctgttatg tctagaggac tagagttgta 26040 ctctgtaatt ggccacacag gtcagtcttt acaaggtgta gcattcagca gtgcagaaag 26100 gcatcctgta gacttgtttg ctgagggtca gagggtaaat gctgttgtga cagttgggtg 26160 gacttggtcc atttctttgt ggagggtgag aaggagatga ggagttacta ctgatcttgg 26220 cgatagtcgc agggaagata agccctcata tcatgtagtc tctctgatat aatttcaatt 26280 catatgaaaa ttttctattg aaaagaggag ctagaaaatc agtcatggga aataaaggtg 26340 atctctagca catgttttct tgcagggatt ttagcccatc aagtctctgt gagcttaaag 26400 ttacctcatg tcttatactg ttactccagt attgccttgc tacacgatca tctctgtcct 26460 atgagcccca gggtccgata acttcacctg ctggtttagc tgcagttttg atgctttgat 26520 ttagggaccc ttctcagtcc ttccctattt atcttcctac tgggaaccag tcacaccttc 26580 tgtgtcccat cgaactgtgg cttgtgactt catattagca tttactttag ctatcatccc 26640 tttcatgggt ttatgtagag atctttactg gcgggatagt tttatgacca accctggatc 26700 atatggttgc ttagatcttt tcatagacca tatgcaggat aatatgtagg catcattcag 26760 caggcaatgt gtagtgtgaa aatgtatgtt tgagaagaaa taacattatc tctaattgat 26820 agtctttaag actcctttaa gacttcccac cccccatgtg tgtatggttt gacggtatga 26880 tctaattagg tcaattaact ttactttttg tctgtttcct attaacaagg ggaagggagt 26940 tgaaggttac gctggcagtt tgcagcatta aaagaaccaa tgcatttgac ttgttccatt 27000 ttggagtgac agtggagatc aacaggaaac atggcctgtg tgctgcttga ggtcacttac 27060 cagcaccact tcacttgctt gagtgccaaa ctattggccc tgactaacaa ctactgtagt 27120 tgctgaatta aaaagtataa aaaggacctt gtgagattta aggcagcaga gaagatgctg 27180 actgtgtctt ctaaatggaa gctcagcctg aagtatcagt gacctgattt tggcataatc 27240 ctacaagccc aggctgcagt acctatacca ttaagtccac cctggggcat tatagctcaa 27300 gcctcttatt ccaatagaat cggtatgaac aaaagtctcc atgagtaaaa agcaatgatt 27360 aaaaaccata agtagtagat tagaatgtaa gtagtactgc cactttgtcc agttatcaac 27420 taaattataa atcatggcca attgtaatct ttcctattct ctgtctgtcc atctgtttgt 27 480 ctgtctgtct gtctgtctgt ctctatctat ctatctatct atctatctat ctatctatca 27540 tcttcttcct ctctctctct ctctctctct ctctctctct ctctctctct ctctctctct 27 600 ctgtcttaca cacacacaca cacacacaca cacacacacc ctatcctttc ctgtcctatc 27660 catctttctt tatctcttat gctaggaata acaaccaggg tcttgcatgc tagatgagtg 27720 ctatatcata aaccctagtg ttttttattt ttcattttgc aagatcaacc atagtgaata 27780 tatgtaagtg tgtgcatgta tgcatgtatg tatttgcatg tacatgtatg tgcatgcata 27840 tgtgtacttg tgtgtatgca tatcatgcat atgtatgcgc atgtacgtgt ccaagaacat 27900 gcacacccat atgaactttt agattataca cactgaatcc tggctttctc atttgttttc 27960 ctctatgatt tgaacataac cagaacattt aaactctttc cattatttcc acttaaagaa 28020 accatttcat tattcttata attactctgt agtcttaatt tcatttattt gtttcagttt 28080 gggtggattc ttgttttttt tggggggggg ttggtgtttt gttttgttgg ttgaatacca 28140 tgccactggg gccccacaca tactaaacat gtatggtacc atggaactat ttttccattg 28200 ctatccaata tgagtgagcc tgaaagacct tccagtcttt tctagaaatt gcatatgttc 28260 ttcaaaggtg gcacttctct tgttgacttt taaagtctct ttctgataga aatttccagc 28320 taacgatgga tacagataat gttttcttac aaaatcaaaa cagcgtcctc cataggctgg 28380 aagatctggc tcagccaccc agtcgccgag gcacacctaa cttggttgca ccacttttta 28440 atcgagctgt gaatcagaac tgagaagctg gaaataagtc aatttactgt gtttgtaaca 28500 gtagaaagct ctggagagta atcttcagca agagacacac tactgaaagg aactgacagg 28560 ctacggaagt ccgttgtgtc cacaggacct ctcagtttcc catgcaaacc atgcaaacca 28620 aatgttactt tttctgaggt tgcattcctg cacactgttg gcacacgtgc aagacagtaa 28680 tctctttggt aatgagcact tggtgccaca caaagtgagt ctgtggggat ggagccagca 28740 aatctgagtt ctgagctcag ctataagtgt aatttatgtg tgaacttcat tatgcattta 28800 atccctctgc aagcctattt ccttatttga gaactgaagc aaaagaagga agacaagctt 28860 gtttcacaca ccagacctct ctttagcaga cctcatgctg attgggactt ttcaagctgc 28920 agggactaca gacctgactg aggcatgacc actgctctca agtgcctctt cattatagaa 28980 ttcgtaaaga agtgaataca aggttccatg atgagatatg cagtaatacg aatttgacat 29040 aaaattagca actggatacc atacaaaaat aagaaaacac agagtatata gcaaatagca 29100 tgttttgaaa gcactggagg tgacatgtga catgagtgct gtgttatttg aattttcctt 29160 tttggagaaa actatagaac tagttggaag attgtgaaac ataatacatg tgtgttgtaa 29220 ggcacaatgt aaaataaaat tctaaggcaa ttattacaaa ctctaagcta ctatgtctct 29280 ctttgtcagc taaggcagct tttcccataa gtactcaatt ggtactatca tagagtaaga 29340 attgatcata agattattgt taaaacccct tcatatatga atgtttggtc ttcttttatg 29400 aaacgaatgc aaatagctcc tttcaaatct gccatcatgg accctgttgg tctttagtgg 29460 atgcaacaaa ttcatcagtg tgttccacat gtgggaaaga caacactgta ctatgacatt 29520 gcattgaatt tatttgatgt ttcttccttg tgtgttctac tgccatcaat ggaacatggg 29580 gcagcctgat gctctgcata tccttcattt gctggtcctc agttccatag ggctccatgg 29640 tttgccatgc ctaattaacc tcagtcctct gtcagaggca aaatggtcaa ttaccttgtc 29700 ttcaccgaga cttccagttc tcatttttct gaatatttca actctctctc tctctctctc 29760 tctctctctc tctctctctc tctctctctc tctctctttt taaatatgga gttgacctta 29820 tttgggggta cactttctag tgaaaggctg atttgagcca cagcatccat gactgtatag 29880 ttaatactga ggaagtaaaa ctgtcaggac tatacagaga tttactggct tcagaaatgc 29940 cccaggactt agccattact ggattcacct gtagagaatc agggagcaga caggcgatgc 30000 caaaggcaag tagaaaaatg actgagtaga ctatcaaacg catttacatg caccagcatt 30060 taatgcttag catcccaagg tggtacaatc ctgagtggcc agaagagcac aggtggaaac 30120 gaggtggcag gggccgtgag ccaaaggtgg tgtatgcctt gtgtagaaga gtcaggcagg 30180 atctttcaca tttcttctaa ggggtaaagt tgccacttac ttaacctgga gctaaggtta 30240 aacaatttga ggaaataaaa gtgaaacctg aaatcatcag gccttaagct ggctggaaac 30300 tgattgccca agttgcctta agcgggaggg agtggggaaa ggaccagcag agacaaatag 30360 ttcacacggg atgttgtctg ttttcatcaa ttataaactt tatgccatag tgaaatatgc 30420 aaatgtaagt tcccaaaact caggaatcct agtcatattc agggtcaaat tgacagtggt 30 480 gtttacagaa cagattgaag actggggtgt ggagagggaa ggcttgtact tggcatagtc 30540 acaaaagcca gatccctgtc ctatgttcag ggttctccag acagagatct cttatgaaca 30600 gtcattacag gcaggaaggg tcaaattttt ctatggtttc agaacgagag ccatgttaag 30660 ctttagtgtt gcattgagat atagttcagt agacctagag agcaacatgg catgttttgt 30720 aattgtccta aatgagcatt tctcatcatc tgttaactaa aagggactag cctaaagcca 30780 tgtaggcccc agaccctggt ttctggctga gactgtagag cactttccct ccatgcctgt 30840 tggcaatttc attgcctggg ctacttagga tggtggcatc tctgtacaca ctgtggcatc 30900 aaatcagaaa gctaagataa gggcagagat acaattatta atcaaactat tgaaacttga 30960 gacactgtaa tgtttgaaaa taagaatagt atttagtagc aaaacacgga gctgtgcaca 31020 ggaataaata agaatgatac ttatatttca tagaatctat catgcaaact atcaatgtga 31080 agctagataa gagagttaaa tataacatcg cataaaattt tgagttttaa ggggaaagtg 31140 ttaaaaatgt taaataaata taactgatat ttgatgtgag ctggtttgat gtgaagacct 31200 gctgtttgta aatcaaacca gtgggtgtgg agatgaacct gtttatttta atgagtaata 31260 ccaagttcca aaaggaggaa gttactcact tatataatga atatataaag aattaatgca 31320 gtagcttttc tattctggaa tcacattagc gttctaacaa atctgtcaag ttgaacaatc 31380 taaaaaggca aacttcttac ttgagatatt ggtaatcaga gggttcagtc cattgttagt 31440 tggccctgtt tttgtctgtt ctgtgttgag gcaaactatg atagcttgag caagtgtgag 31500 aggaactctc agttcaccct ttaacaccta cttccagctc agctccactg ctaaagctcc 31560 aggccctgaa caacagtatc agccagggaa taaatctgca acacatgagc atttgagaac 31620 catgtgagat ccaaaccact gaatgtggtt gaatagaagc tatattgctt agagtacagg 31680 gaacaatggg tggtagctat tagctttggg catagtgtgt atatatctat ggcttttgtg 31740 tgtgtgtgta catcagaata ggtacatccc caaaagatgt tttgaggatt ctctggtctt 31800 tgcctctcat atcactgtaa gaaaactgtg atgacagacg tcagacacat catagtacac 31860 ttgaccttta catgagtttt tgaaattaca aatcagatcc tgcttacaca ccaagcactt 31920 tgccccatga actatggttc tacctatgca atattatctg ttagttgaaa tattgaattt 31980 atgctctgtg ttttacataa tagcctatta tattgcttta aggccataac atgaacaaat 32040 atacctttaa tatttaagaa aatatatgca gtatgtgaat catacataat gatatgtatt 32100 tgtccctctg gcagagtata tatcaaaatt taacaaggga tgcctctata ttctagaaaa 32160 tgtgattatg ttttattctg tgtactctta ttttatatat tttaaaataa tatgctcata 32220 ataggaataa gtaatacaag tgttacatcc caaagaagtc attttattta tacagtgatc 32280 agaattctta tgtccatttc taatcaaaga ggaagtaact tgttattatt tgatcagttt 32340 ttttagcatt aatatcatta taaatagcga gaacttacca attcaatagg gtggtgttgg 32400 agggccggca ccagctattt tcagagcaat tgaagaactc ctggatgggt ttggtggctc 32460 acgcctgtaa tcccagttct gaggatgagg gaaggaccgt tgcaggatca aggcctagtg 32520 tgcacattgc cctcacctca ctgcaaaaag gtaaataaat gatgggctac aaaggactag 32580 tggatatgga aacacaatct cacccccaag caaataatct atgtgaaaag tagaatttct 32640 cttttcattg ttaaaggtag aaggatgtct tatggtgctg tgatgggtcg agtcttctga 32700 atgtttgggg actatgttct tggaaattag gatggtaccg tagccagtca gttacttagg 32760 ccataacagt tgtctcagca cttccagctg tgtgactctc taccaagaaa atggccaaaa 32820 tgaacaaaat gctaattaac aaacgtaata ttgtatagca tgttagtttt ttgctgtaca 32880 taaacacagg agaatgccaa agttaataat tgtgagtgac gtgcttatag taggctttta 32940 aacattggcg ttttcaggtt ttacttctag ttatcagatt accctttaat ctaattttct 33000 atcataatga agaattatgt gaaagatgat tacacctctc catttttaca tctattgaga 33060 tgtagaaacc ttcaaaggcc aagcattatc taaaagcagg gatgtgatac ggtttaaatg 33120 cggctattat tataatcaca gagtccgctg gataaactgc aggctgctgt ggccatggca 33180 ttggagaaag gtaaaccaga gaatgggagg agatatgaag ctgcagtcga tcatccatca 33240 gagttgcatg cagagttggg ggatcaaatt acagattttc actgtcacaa acgtctcctg 33300 gtacctcaat gtgttcatct gttaaacagc attttcatga gaattaaata aattttatat 33360 atgtaaataa aacatttgga agcatacttg gcccagaaaa agttccagga cagacagaga 33420 gactgacaga gagaaagcca cacgcgcgcg cgcgcgcaca cacacacaca cacacacaca 33480 cacacacaga gagagagaga gagagagaga gagagagaga gagacttgat gctctctatt 33540 attttacctt ttataatatt tattaaaaaa tcttctatct tggacacaac tatcagattt 33600 gcacagaatt tcctgcccca ttggtgttag aaggcatccc cacctttcag agcctatatg 33660 gtaactctaa aatgggtgtg tcctactatc ttgaatttga atgcaccttt agataaaaga 33720 ggaagttgat caggtgactt cagcagttta taaaagtgtt cattcttgtc accagtgtgg 33780 cacagaggaa aggaaaccag ctagctgagg gaagatggga gtctgaagag ttactctgtg 33840 tgctctgtca attccccttt aatttggatg ggagctgact gacatttaaa gatgtgcttg 33900 atttggtttg cagcagctcg gaaagtcccc acagcccaga gcttcctccc aggctcttaa 33960 aaaccccaac ctcttttgga ctctcaccgc cttatcaagc tggcgggttt ccctctccac 34020 aaatgattat taaggatttg agatgttgag cttagatcga agtcattctt tttcctctct 34080 attttaatga actactgtgc tgtgattttt tctgggaaaa gtattccaca aaataagtgt 34140 tcatttcata ataagctttg ggaaagagtc tcagttccac tcacttattc tttcttctag 34200 aaggaaacta aaataccggg tgatggtata ctagacgtga tagaaatgaa aaaatttttc 34260 taacttcaaa catgtatttt ttaatgaagg agtaagcgat acttttattg aaaggtagca 34320 ttttataact gctttcttta gcactgtata atgtaagatt ttacttcaac taggagattc 34380 aagaggtacc tgaaagatag ttttaaaagg atatcaaaac aaacacatgc atcaggtgaa 34440 cattgagtac agattaatgg aaagcagaaa gagagaagga ggaggaatgc ccaatgaaga 34500 agctgatggg ggagggtggc aaaagggggc agaaagggcc tccgcataaa ggacagagtg 34560 ggaagggtga agccctcagc agacaaacct gggaccatat ttcaatgggt tgaatgtcat 34620 ttgtaaatag ctgtctatcc tattagaatt ggggtaccct gtgagtgccc cctcactttc 34680 tccaagaaag gtaaaaaaaa aaaaaaaaat gactacaggt cccagaagat agaagacact 34740 gcattttgtc ccttttactg ccttgcccag gtactttgtg gctaagacat agaaagatta 34800 ctaaacttaa aactagatac acacttcttt ctgtaagttt taagcattgc aataaaaaaa 34860 caaggtgcca attattggtt tccattggta aataaataac ccccaagtct tggcttctag 34920 tgtcccttgt cttctaagtg aagaaatgaa ttttttcagg aggaccacta ccaggtgcat 34980 ggctatgctc cccaatgctt ttcccgtcca gtctctaact ccagccatgg gacagactta 35040 ctgtttatac acaaaacatg agtgcatgtc tcatcttcta gaggtctttc tgtgccatgc 35100 tgctccccag tcaactgtgc agggccttct aaaccattgt gctcccaggg aaagcgagca 35160 cacggaactg ttactctcct gtaactacca gcttgattaa gtgcacggtt cttccatcca 35220 ggatgctaat tccaaaacca aacattatca gatatacttt aattagcact cttacgaata 35280 tgtttatgtt aaattcaaat tgatactgac aattagctaa tatttcttcc tggaaatgtc 35340 ctaaagcaaa cataaataaa caacatgcgt tttacttctc aatacattgc ttcttttttc 35400 tctgtcccct ttaagtattt acaattctac atggcttagc ttcttcattt gtacaataca 35460 gagataaaca aattgaggga cagctatcaa agcaaaatga gggaactctg tgtagcactt 35520 ctcttaatcc taggcaaaga cacagacttc cctctttgta aaggtcttta ggaatcctga 35580 gctctgacac actgtcattt cccaaatgag gagtctgtat ctaggctggt tgagtaactt 35640 gcccctagga catggagctg gctaaagcca gaactggcaa cacaactctt gtctctaaat 35700 cccctgtcca ggttcttttc ctcagctacc caagcttcta aaacagccat ggtacttggc 35760 tcttagattc ctgtctaaaa tcttggccca tgtctgacag agaccacagg ctgatctgtt 35820 tgtgtgtgat taacacatag aaggaatgag acttttcatc tccaaatcct gctgggaatc 35880 ttttaacttt gttaaaaaaa aaaaagttta tcacttgatt gtatatcatc aatagctcag 35940 ttaaaggatt caaatgattg tactgtcaaa ttagtataaa aattaatgca gtatcagatt 36000 tactttcaaa cagctattct cagggaaaat tcttttgaga ttaaatgata ggttgaataa 36060 aattcctttg ttgagcctac agctcctgga ggatcccatg ccagggatcc cggggctggg 36 120 tccaatactg gctttgcaaa acattgctgg gatcatgcaa cttttatatt cacccttaac 36180 ctgtccgtgg aagtataatg gaaagatgtg gattaaatga ttctactata ttttttagtg 36240 cccccaccca gttttgtttg gttaacgtaa ggtaataaga aacataattc cttttcgtat 36300 ttaagtgagg aagtgaaatt ttgtgttagg tggttttgca gtatttaaaa tctcatatgc 36360 ttgaatattt gagattaaat tatatatggg agatttttct ttacagaaaa aaaaagcttc 36420 actattaaca attattcatg ggtccttaaa ttaattttca ctccaatgac cgcttcatcc 36 480 ttctcccaat gaggtttaga aatgcaaaat ggatgtagac agaaggcaaa tccaaattca 36540 taaacatatt gcaaacacta atcctggtat ttctatatag taaaatatta tgagatctag 36600 atttttttcc agaattttaa tcccctaaat tttagaagaa atttaacatt cactcttact 36660 agtcttaggc agttagaatc ttaggtacat tagagaaaac tgtgctgcgg atttcgggag 36720 gttaatgttc agatacgagg ctagctgaat ttttaagccc caaataataa tgacagagtg 36780 tgttagaaat tacgtcagaa tttgggcaca ttccatcttt cctacgccaa aaaaccgaaa 36840 agagtttata agaatattct tatgtgttta tgcaaatcca tgctattatg ttcaaagata 36900 gcctttttag tcatttagat agaaacatga caatcaattt tattatacat gtataataaa 36960 taacttctct gaagccttaa gagaaactaa atataacaga gaagagaaat atataagtag 37020 aggagggtta gggggcatgg ctatacttcc cagggcttct acataactat atcttgcatg 37080 tatgtttgtt ttttaagtct agtaagactg atggtttgaa ttgcttctga aacatatttt 37140 gaacaggcaa gtggcttaca ttgtttgaca tgaatctgct ggtatatgtg tgataagaat 37200 atattgaata cttgagctaa caggcagtat ctttaggagt tttatattga gaaaatacac 37260 atgtaatttt ccctaatctc taacttcatg taatcattct taaaaatcca aaatgcaggg 37320 ggtaaacaaa cgtcttccaa aactttcaca gaacttctct ttctcaacat gaaagtgtag 37380 taacaacttc gtgtcctgcc tgcctccctt ctgtgtgtct ggtgggggtg gtaggtttgt 37440 ttgggggagg ttttgttttg tttttaggac agagtgcact ttcttatgaa agagacaggg 37500 aaagttttac ctgtctgtct tctgttctct ctctctctct ctctctctct ctctctctct 37560 ctctctctct ctcttttctt ttaaagattg gtgataagga attctaacta cttaatgaga 37620 tgggagaggc ctcactccat tggagtggag gagcccaggt ggaagttgat ggattggaca 37680 ggtaaagtga agagtcccgc ccctcatgcc tatagttggg tatatattag tgaaccttaa 37740 agtatgtaca gagagagaga gagagagagg cacctgaatt ctgttatctt cttagaagat 37800 tcgcagcgca aggctctcag agggggtggg ggggctggca aaaccctgga agcagaaaag 37860 aggagagcag ccttgaccag tctcactgct aacatgttgt acctggaaaa caatgcccag 37920 actcaattta gtgaggtaag gctttaagat tttagccctc tgcatagaga tccttttctt 37980 cgcttcttct tttaaataaa aacatactta gctgtggttc tagtgaccca atgtaaatgt 38040 gtttgcaagt cgcatgtagg aaactgcttt tctgagtgaa tgttttctgt agtgactgta 38100 agaatttctt ttattttctt tgaaatatca gatgaaacag tagaagaaaa gggaaaacaa 38160 aaaaattcct gggtgacatt atgtattcga agaaacacaa tattcaggat tttacaaaat 38220 cgcttttctt ataagagcag cagcggaagt agagaagacc ctgctgggaa tattggtggg 38280 tgtgaatgta ccagtgatag aaacgaattg attgtgtatt aactgtatag taaagttctc 38340 caggcttcat actaaaagga aatggatctt ttttttttct ttaagtaatg aagtgggttt 38400 gtttaaagct agctctttta gatgtataag tcccaggagc tcatttaaat gtaaaggacc 38460 ttgagtatag tccgcactgt gaggtgactg aggaagaagt ttactgtaga tggacagaca 38520 agttacttca ggacagtatg ctattaacca ttgatatatt tgtctctgca tgtgtgtgtg 38580 tgtgtgtgtg tgtgtgtgtg tgtgtgtgta tacgcacgtg caaacaaagt gagtatcaga 38640 gcattcagga ttttaatgtt ggacagtcct ctgctttcag caagtttgac ttagggattt 38700 aaatcactgg gctacgggga taagggagat ataaaccgct ggtcagactg gaggctctga 38760 ggatgtgtcc taaggctggc cggcaaggtc taacaacaat attagtttac attcctagga 38820 agaggcagct gtgttgacac tgatctgatt gggagggagc aggggctgcc tgtccagaaa 38880 gagtccagtc tttcctttcc gatgggaacc ctcccaggtg aatgcttgtt ttaaaagcgt 38940 ctgaggtgcg gggaatctag ctccttaata gccaaaacaa accatagcac ccagctccca 39000 ccgcaagagg atgagaagga aagggccgta gagcaaggcc agtgctgtgt gattgaccat 39060 gctgttgtct agacacctga actgtgcaaa tataacaggg gaaatatcaa gttatctcaa 39120 ggaggaaaag gaagttcctg ctttccttta aaccagacag gcagtcttgc ctgtccttgc 39180 tagaggaact cgagtttctt gttttgcttt accattgaaa gggagcttat aattttagca 39240 aacaatttta aagaaacgct ataagttgta tgtgcgtctg gctctttccg ccgcgtccaa 39300 tgttgctccg ttttcataat taagaaacga tcagtctgtc catctaattt catttgtatt 39360 tgttaagctg ttttgtgcag taattttcaa gtgtctagga gctgtctgtg tgaatgtgaa 39420 agaggaaagc aagttaattc taagatatgg gtgaggatat tacaagccta gcgccaaggt 39480 acaaagaaat gattgtctta aaaaaatagt atcagaaaag aaaaataatt ttaaaaaatg 39540 acaatggtat atatcttcgg gaaaactgcc tttcatagaa atggtaattt ttatgtgcaa 39600 gaatatggca gccttatcat gaaggaaata ccactacaca ggcttttcaa atgctacaca 39660 gagtacagtg agggtgtcgg aggctgatgg gccagctgct ggaatgtact gtcctagaag 39720 acagctacaa agaacatggc tgaacttcct gttgtctaaa tcattttcct cacttgcttc 39780 atggggcctt cttctcttcc atcagtgtat gcattatgtg gtaacttcat ggccaggtcc 39840 tgttacgact ggcttccctg tctgtgcggg cttctcatta atatctagtg ctgcctctaa 39900 atatttgggt ccacttgctt ctgtgactat ggagttttaa taaagaacaa atggcacttt 39960 gatattcatg ttcatctgta cccatcaaca tagaaatagc aagaattgtt aaacctggat 40020 agattgagga tataaaagga atgtaatatc taacaaagat tgtttaataa ctataatgta 40080 ctctgactta aaataatttt ttaaacttac tgggaatttg agttgataat tcaaagatta 40140 gtaaaggcgc agcatgttcc ctccctgtac tctcttcaac tttccagtta ttcccctgca 40200 gcagagctgg acttaggaaa gctgctaaga gcaggaaagg gtccagaggg aagacggcta 40260 tggcaagaag tgacaggcag ggcttaaagt tgtggccttg tgtgacaatg gggaagtaac 40320 aagcctgcac tgggacctag tgccaagctt gaaaccatcc cagattcaga tagagtgtca 40380 caaggaagga atttcttccc agatcaaact ctactttcta aaacaacaac acaacaaaaa 40440 ggaacgaaca aacaaaagcc ctagactggt gcccccaccc ctgcgtataa taatacatcg 40500 gtatctctgt gtgtgtgtgt gtgtgtgtgt ttttgtttat gggcaggctc atgtgtgtac 40560 atgtgtatgt gtgtgtctgt gtgggggctc cttatgtgtg gggtgggggt gggggggaag 40620 ggtggtgata gggtagggaa gagagaagat atgaaaagac aagaggacaa cttgtttcag 40680 gaagatcttg ctgaaccaac cctagttgga gagggaaaag gaccttttgt gaaatgatac 40740 taaatagaga acaagaatca aacctctcca ttttactact tggagtcgat gtttctcatt 40800 tgtatttgag agtgctctat gtatgccact atgtactatt tactacttgt atctggcact 40860 gtgtggagca gctctataca ctctgaagag gactgttgta actcagggag ctgcccagag 40920 agatttccat gaagtactta tgcaatgctt cggggaaagt gctgtggcag cagctagagc 40980 cctgggcagg ccaggtcact gacctcgggg cctgcatggt ccaggcaggc aagctttccc 41040 tatctctggc cttttctagt ggctgtattt taaatggggg gcagtgttct acttctttgt 41100 tagtaaatgc cagtcctaag ggttcccatg cagggcttga gataaggaac cttctcagac 41160 caagaacagt ggcaggcatc agctgtagat tgactacggg tgtcagccac atagtcactc 41220 acgaggctgc cttgccctac ctgttttcca attgagtgcc ctcaagccca gaagggactg 41280 ggagaaagag atcttagatg gcagatcata gatcatacct tcctcgctac tattggaaaa 41340 gagatggtct aataaagaaa cacttatcct ttatctagat aaggggaagc ttgtttgttc 41400 tggttgtttt ttaggagagc agtgatcctc aacaggggtg tgtgtggggg gggggggggc 41460 aaaagaatga atgaatgtta cccacagcag cccgacagga ctggctgttc tttccgcaaa 41520 ctacattcat ttcttagaca caaatcggcc acaaactttc ctaggtttga acacaggatt 41580 tagaatgaat tccgtactct gccctgttaa tgaaggatgt gtctgtggcc atgagatgtg 41640 gttcatcaag gaggatttga gtgaaaaggc taagaaatat gttaccacta gctttctttg 41700 gtgtgtgctt aggagaaagg aacgtagggt aaaaatatct tctcttgcag ctatcaagtc 41760 aaactgtttg ctttgttgtt gaatgttttt cacctttgat tttatattga taataaaaaa 41820 gggatagaga cagcactaat gatcaaaaga gaactcagtt aaaaaagaaa gtcttttcgg 41880 aattgccata aggtttattt atagttgtac ttgttttgaa gatggcagtg ttttctaaac 41940 ctagtggact aacccctctc ctttgatacc tgacgacaag aaggttgggt ggtgggcaaa 42000 ggtgttctct atcatccatt gctaatttta acggtgctta tagagagtat ccagcagaac 42060 aggggatttg ggatttagaa cacaatgact tgaaatgtca aaaggaaagg tagctactcc 42120 agaagttcat ctgattcaca gtggaagact tcagtgcggt agggaagtgt aagcaaaatg 42180 caaagtgtca gagcagaata aaaacccctc ctaggacaat caggaaatcc catatgtata 42240 tgctggatgc agctgaactt gaagggacag acagagctct cttaagtcta gacttggaag 42300 aaggaaggaa gattttttta agggaaatga taaaacacag aaggcacacg ggttgggtgc 42360 tgactggcat gctcagaaac gtcatgtagt tcaatggaat agaaagtatg gagtcattag 42420 gacataaggt taaaaatatt agagtggcta agcaaggtcc atgctactga gaggggagtg 42480 tgttgacagt ggtgtggcaa atcaaggata agctctgagc agagaactgt gcagtcggaa 42540 ctctgtgtga gagctcctag ggaggaaaga tgaaatggct tagccgtgaa ctgcatggaa 42600 gtagaaaaat gcatttctca aacttgctac acattgggct tccagttctg tatatttaca 42660 gtgagctttg ctgtaccagt tggaatagca gaaaggaact ctttcccaga tctcactcaa 42720 ctcatgtatg ctctgcccat agctctcttc aatagctggg gttcctgcca gagataaatt 42780 gggaatactt agtcttgttt taccctgttt atatctgcct ctccagcaaa attattaata 42840 gcactccttt tcatttgcaa aaatcttcta gttggtatac aaattatttg attactttaa 42900 aaatggactc tattattttc atatttttcc ttaaataaac tattcccaaa taagaagtaa 42960 tatatatttg ccagtggatc agacatcagc cacaatccac acaaatgttc attttcccat 43020 taaaaaagaa catttctgta tgacccagta agccctgaaa actaacttta gacacatgga 43080 ctgttctcaa aaggaaggca ggagtgagta agtagtagcc agattctttt gagaatttgc 43140 cagcctagga aggacagaat gtgctcataa atgattccaa cataaaacta gcttaagagg 43200 cacactgtag cttctgagag agagacagac agaaagagac agacaaaagg acaaagactg 43260 agacagaaag acagagggga gagagaacat aaattagttg tgattatttg tgaaaaatat 43320 ttcacattag agcttctata attcagcaga taatggaggg ttggaaatca gtgtgcaaag 43380 aatataggta taaagttaat aaactaaggg aaaacagaat cagttcaagg catacttatt 43440 tcaaaagaaa gtatattaat tttatatact tctcagcatt aaaaatgaag ggctttcaca 43500 gaaaccgtga gagagaacta caagggcttt tatgctttga aacatgaatt ctgttcacaa 43560 gtttgagatt gctaactttg atgacacact ctggggtgct agggggcaca ctatagcaaa 43620 agagaagaat tagcccacag atgacttgag ctggaaggca tggagaatca cctgtttagt 43680 tccatagact tcaatggaga tagtgtcatt agtttataat cagaattagg gacaaagttc 43740 agatggtttt ctttgttatg aattaattat attttctagt catcataggt ccaggataaa 43800 ccttctattc tggcctcttc tctcaataaa aattgaaatt ctagagataa atatggaaga 43860 ccaaatccat ctgtgagatt tgctcaacat gagaattcca gttggaaggt ttcagagcag 43920 agagatattc aggtggcaat accatcccac cccaccacca agttaagaaa aacatacgta 43980 acacatttag tctttaattt ctcacataaa tcatcttacc catgagagtt taaaatttta 44040 tttttggggg gctggggaac aatagcatct gaaaagtcat gttggtgaat agacctatct 44100 ttgtctgcaa tactgaactt cccttccaca gtccctaccc ctgaccccat cactctattt 44160 ctccaaggaa gagatgcaga caactgagag agaagcctag aacagcgaga gtagtaggac 44220 ggaccatgga tggatagatg ctaatggggg agttgatgac ttgatctaaa gacaaagaaa 44280 agcctggtgt ggtgtagacc tgaaactcca gcactcttaa ggcagagacc aggacactgc 44340 agtaagtttg aggctacccc agtctacact gcaagttcca gcaagttcaa gctagagtct 44400 gatttttttt ttaaaaaaat caaaatgaaa tagataaaaa tcaagagacg tagggaagaa 44460 gggtaggaaa gagggctgag ctccatgatc agtggaggaa caccccagct tgtctcactc 44520 ccctttctct tcctttccca tatacttgat tataccaaac atagtccaaa agtgcccaaa 44580 ctcatcatct ttttagccct gtagacttta aggcatacag aagagtttca caaaatgcca 44640 tctgtcatcc agtctccttt gaagaaataa ttgagtgaaa tgtatacagg gtcttcacaa 44700 agacaatgcc ttataattta cacttgattt tcttacatga tctggaagtg ttctattcaa 44760 aatagcattc ctctccattt cagacatggg actttgtttg tttgtttgtt catttttcaa 44820 gacagggttt ctcattgtag ccctggttgt cctggaactc actttgtaga ccaggctggc 44880 cttgaactca gagacgctcc tgcctctgcc tctggggtgc tgggattaaa ggtgtgcacc 44940 actacccgcc tctgccatgg gtttttccat ttctaaactt acttgatgtt gtactgtgac 45000 caactcatga gccctaagtt ttaaatgaag tcattcaaaa agaagacaaa gtaaggttgc 45060 atgactgtag atgtaagctg agatggcctt cccagataaa aaactgtttg tcaatttaaa 45120 attgagcagc tggcgttaag atgaatcaca cattgatcat gggaagggga ttaactttga 45180 aatatttttg aaaaaaattg atatttcatt caaaactttt aacctgaaca ttttttcttg 45240 tttcctgagg gaccaaaaaa aaaaaaaaaa agttgggggg ggggataaaa tatgtataaa 45300 agctgtggtg ggtggccaga ggtaaaaagt catgaaccac tctcatcagc cactctggaa 45360 acactacaaa ggaaatagtt cccggttctt attggtgcag aagccactaa taggtgcagt 45420 tagtataata cccctctgag aattaccacc cccaaagagg gcttgcttta gacaggactc 45480 tgcaacagcc ttctctttct tcctttcaag cttgcgcaaa acccccacag gggccatttc 45540 caaccaaggc agtgatcttt cagaggctga ttctttctca gatcacagag acaatgggga 45600 atatactctg tttactcaaa tcagtctgga ttagtgtcag tctattgatg gaatcagaat 45660 taaaaggaaa accattaccc ctcacaaaag gcaacaacat cagatgtccg ggggatggct 45720 tgactacttt taagcagact atgggagaca cttctcagac taaggtagaa gacccatcac 45780 acagagacac atggcaatac caggtgaggt aaaggcagtt cttctaagca tcgcgcgcac 45840 acggggaatt atctcagcag gcagtgtcca tgcactaaaa aggccaaaaa cctgactgag 45900 gaggtggagg gagagactcc ttttcttgct tgctatttgt accccagcct tcacaggccc 45960 atctatatat ctccagatgg agtcctttgt agtcattaat gctttctggg agaagtactc 46020 tacccatgga gtcccatgta actgacattc agaacaagag ttctttctgt cctccgaagc 46080 cgtgtgcacc acatgctttt actctgtcgc tagtttgaca cctctcaaat gatagggagt 46140 gggatatttg cttctgagtc ctctacaggg ctgctaaacc attttctctg aacggtttgg 46200 atggccattt gttgctctgg cttcaactgg tatattcaga tagaaatgtg gtttttggta 46260 tctcataaaa ataagactat ttttaaagcc gggcgtggtg gcacatgctt ttaatcccag 46320 cactcgggag gcagaggcag gcagatttct gaattctagg cctgcctggc ctacaaagtg 46380 agttcaagga tagccagggt tatacagtga aaccctgtct cgaaaaaaaa caaaaaaaac 46440 aaaaaaaaca aaaaaaccaa aaacaaacaa acaaaaaaag actattttta aatggcaggc 46500 aaaatactat aaatatgcaa ggtttgtcct tggtatattc tgtaggtaac cgaaacacat 46560 ggtttttcct gatgtctggc aggatatttg gttgtttgat tgatttttgg gtttcctgca 46620 gtatggggag tttaactcac ttctgttaaa atttcaagcg gcaagaaagg tttttgaaag 46680 atgggtcagt cccctggctt aagaatgggc tgtactctta acaggtaaac agggcagagt 46740 acatgctact ttcttataat tgattgccta tgagagcaga gaatgtgtgt ggttaaaagg 46800 gagcgagaga ttagattttt atcttgtatt gcagttaaag tgtttactta ctcctatgct 46860 gatttcttga ttcagtctgt cccctgtgtg tctaaggcta atcaccagag atgtggatag 46920 tttaatgtgg gtgaatgagc ttggtgactg gcaaacaccc tcctctgatt agcttctatg 46980 ctctgaaaaa tccgaagtca ttttgcttaa tcatgtcatc taagcctttt ccctcctaga 47040 cgcccactgt tgagccggat gacaaagggc cactttttga ctgaggtcaa taaagtgaga 47100 caaggagcta aatgacctcc agagtgaggc aggccttcgc cagagctgct aacttcagtt 47160 ttgttttgca gtgagcagtg acaggttaga ggaggacccc aatgccagct acgtcacact 47220 gtctaattac aaagtatcgt aaggcatcta aacgtttacc tcagatgaaa tgaaatatgt 47280 agcaatcagc caggcagctg acaagcaaaa gtaaattaga gggctagcgc agagaccagc 47340 agcagacccc acatttgatc cctggagctg aacctcgaag acaaggaagc aaaaatagaa 47400 tgagaacggg tggccctgtg ctcttcattt gcaagtggca agactcagga gtatacttgc 47460 ttagtgctcc agtgtctacc ttgcaactaa cgattgctgg gtaggcctct gggcatgtgg 47520 caggtagaga gcctggaagg tcatgcactg agatcatttc caagaaacag attataagtt 47580 tgataagcca agtcttggct cctccaaaca aacatttgta attcgtcaat cctgtcactg 47640 ttctgaaaca gagtgaaaaa ttctaaaatt ttctgactat ctaggcagaa aattgtacaa 47700 gtcagacagg gctaggccaa gtcagtggcc tattagaaac taaaggcatc tctaagcttt 47760 tattcaagta gtttctttcc aaaggaacct atatttgccc gtaattgtct ttagtaggac 47820 gtaaataata aaaacaagac catcaaaatg gagagtcata tggctgacct acatgcattg 47880 aaaagaaagt ctagaccatc aggttaaaaa aaaatctttg ccttggcaca aatgtgagtc 47940 tgtgttcatt ttcaggaagt agaggctcct tattaagctc ctcggttagg tgtgagccac 48000 cagctattac tcactgtgag tgagtgacaa ttctggctct tctgctgtga gttcccacca 48060 atgctgaagc tcaaacaaca attcccatct acagagagca taaaaaacac aaagcaaagg 48120 tcagagagat tataggagat gccctatatt ctcagctgac agatgggcac agagatgaat 48180 gcagtgtgaa tgcagagctg cttgagggta agccaggata gcttagttac cttagaataa 48240 ggaagagatt ttctgaatgt gacttaaagt tgaaggatcc tgtacttgtt tttgaaagaa 48300 cagattcctg acatctgctg tgccacagac atttcttcaa gtaagagaga tttgtccctg 48360 actacaatac atatgatctc ccatgaattt attgtctggt ggagcagacc aatgtttata 48420 atatttactg actgcagttg caatgataat tatgtagtac caagaggaag ggatgtgaaa 48 480 atgggagtcc aaggtgggct catctgtctg ggcagtgaga cagggtgtgt gcagaggaca 48540 tggaagcaga aagttaaata ctgaagcaag agttcacttc tgaaaagttg aagggagggt 48600 catttgccaa agggaagctg tagtgactac ctctctggtc agtttaaaga taatttcttt 48660 tttattttaa tttttattta ttatatgtaa gtacactgta actgtcttga cactacagat 48720 gaggacatcc gatctcatta cagatggtgt gagccaccat gtggtttctg ggattgaact 48780 caggaccttg gacaagcagt cagtgctctt aaccactgag ccatctatcc agcccccaaa 48840 agataatttc ttaagagaat attgattttt ctcttgggac tcaatattca gagtttaaga 48900 gtgccatgaa tagatttaca cagtctttcc catggaaaca ccaaaaaaaa aaaaaaaaaa 48960 aaaaaaaaaa aaaaaaggaa gttccaaaga gctactcttt ctgtaattat ggattaagta 49020 gaggaatcct tagaacagga aatggcttac tgggaagggt ggaagccttt agctatatga 49080 aaagatcacg ttccttaaat gtaaatttaa gatgagtatt ccaggcagac attcccaggc 49140 acacagaaag aaggccaatg agatgattca cttcactctc atcacactgt ggctcttagt 49200 gtaatattga gcaaattatt ttaacccatg agctccagtt ccttcatttt taaaataaat 49260 ataaaatgtg aatacctatg aggacacatg aagaccaaga atgcaaagcc cttgaatatt 49320 ataaagccca agatgaagac tccaaaggag tgttaacatc aataatagct aatatctttc 49380 tgcagagagg tttgcatatg aatactaaac acgtatccca ttttagtgtt tactatgggc 49440 agtcatcatt atttattgaa atcagtgtct tccaagtcat gtcagcatga gctacacatc 49500 tcctgcaatg taatcgccct actgttttat gtcatggcat tggatgtaga tgaagcagat 49560 gaactgagaa tggttgatga gttctgcagc cactgggttg tatttcccat gtagatggcc 49620 ttactcttac ggaagatctt cattatcgtg aactgccttt ccccaacatt accccatgca 49680 taaatagagc tagcaaaata tatgcttact ctggacttat gatgccttta cagagcaaaa 49740 cagaaaaaaa aaaaaaaaaa aaaaaaacca aaacccagcc ataaacatac ttctccctga 49800 actttaatga gtagctgaca ggttcaacac actgaagctc tgagtatcct tctctaatat 49860 gtgttaagaa ttatgaaact aattaaaagt atatttctac tgtgcatcaa gccttcattt 49920 tcttggtgta tagtggtgtc agccttgagc ttcctcgtga tttgtacatc tctgtcctga 49980 ttaccggggt gcatacttac taaagccctg gagttaaaat ttccctctct taactgaact 50040 tcagacattt ctctttagct aaatttcggt taagttttct cttcaatgtg ctccaccttt 50100 tctacctctg aaaactctct gagtagtttt tgttgacatg tttgtctctt tgacacccaa 50160 acttaatctg tttgtctgac ctgatcatgg aggttttaag gacatctctc atatatcata 50220 gaattttgtc cctccatgat tcttgaaact ttatgataaa atattctagt tggtactcgg 50280 cctatacttt aggttttgtt ttcacttaaa tactttattc ttacattttg ttcattatgt 50340 gaatggataa gttttatttt cagtgactca ttttttatga ttgtatagca accaaaaagg 50400 aaaatacctt tttcttaata aaatatggtt ttcagaaaag atgccaggac ctctgtgttt 50460 aaggtagaaa gatgttgatc taacagaaca tcctactgta aatatcttct tgacctgaaa 50520 cagaatgctt tcagttaatt atgttcaatt ctagcataaa gcaaaccatc attttctgaa 50580 gtaggacagg tagcagaagg ttgaaaaatg gcaagcattc ctcccttagg ctgtatttgt 50640 tgaaaagcac tatcctgcta atattattgg atcaaaatgg agtgccgtgt gctaatgagt 50700 gaggaatgga atgaaggttt tatgaagcca aggcagtgaa gaaactgttt tcttttccca 50760 agacagctgt agaaggctca caaaggaccc tcgttgaagt ctgaggcaaa agattatatc 50820 cactgaggga actatgccac tgagacagat ttttctttta aaatttattt atttagggtt 50880 tgaccaggca aatcttaaca gagacaaaaa tgatgactcc atgcacctgt tttgaaaata 50940 ggatcatagc cccattttaa aatagtgtct cagggggcct tatagagtgt gggaaaattg 51000 gtggtacctt tccattgtgt ttatggtttc atgaagattc ttagcccata ggaagctggg 51060 gtcaaatttg ctcaccttcc tcacccaggg gaagagcaca tagctggtaa tgtcaagact 51120 taagcccttg ccgccaggac tcagagtttc gttacactcg aaaatccaaa cagaaatatg 51180 agaagcactg aagaggtcta atccccttac ccaacagtca ttcaagagcc aaaaatattt 51240 ttttccaaag gaaatacatt gtttattttt ttccacaaga tctcaaagta tgtagcatag 51300 atggcaatat ctaaagaaga gagattggga tatttgcctt ccacaggtaa atatggggac 51360 aagatatgtc ttttgatttt tttttttcca cacacaactt aagccccatt tgtaaggcca 51420 tgttcaaatg acttgttttg atactttttt ggtgttaatt tttataagaa ggtgatatat 51480 tttgaacttc aagtgactat aaattgaggt gtttaagata gactttgctc attacaacct 51540 actaaaacat tactgagctt atgtggaggg aattcaggtc tataacatgt tcaaaatcta 51600 aaatggtcac tgaagaaagt aaaataaaat gaggctccag gggttgtatc cttaagatat 51660 tgtaacagat aagacaaaga aaactctagt ctgatgctct cttagtcctg gacatccgca 51720 ttgaagttta gtaggataga gatcagagtc tattaacagc tgtagatgca gaccgtacat 51780 ggaaggaaga gaaagaaaaa cttctcttcc ttttatgttg tgatttatgt tctttgccca 51840 tgatcaaagc caacagattt ttcagccatg aggatcccta gttctgtaac aaccatatct 51900 gtgtccccca acattctaag gttgttctgt aacatctcag agggtagcat attcttggga 51960 gcgcatcctt gcggcgtgaa gatcagctca tttgtgatga aaatgaatat gcttcagggg 52020 aaagcaccgg tgatactttg ggtccagtca aggagtattc tatttccaag taacttgtat 52080 ggaaaataag ccaactggct aaagtcagag gaaatcaact cacttattat atgaggagta 52140 catcaggtag cagacaaatt gtgcccattt tcatgttcat attttctgaa aaaaaaaaga 52200 aggctttctc ttctctcaga tgtgacagga caggcttata aaaattgacc ttccttcttt 52260 ctttatgtgt gcacagtatg ttagggatat tctgagatca agtaactttg tcattacaaa 52320 gagagactct cctctatact tcatttcaaa taccatggca ttctttgtga cataggaaac 52380 acaaatgccc agtgaacttc ccagggcagt gtttgtgtcc agtgcacaaa tgtcacctca 52440 tagtctctga cactcttcct tgtcagcatc aacaatcagt tagcattcca gcagaactca 52500 tttcttctct gtctgctcct gggattaccg agaagaaaga agggggcagt attatttcct 52560 cttctccacc agcttccctt tgctggaaaa tgattcttct atcacctacc cagtttcaaa 52620 gaaagatggt ttatgctagg attaaacaca gttaacttaa gacactccat ttgagagcta 52680 taaggaacat cttcaaatgc cactgggtat ctcttgactt tctaatatca ggcattacaa 52740 acacttaaca gtggatgaag aggccctaag gtttcatctt gcactaagca ctagaattta 52800 ttttccagtc ctgtctggag aacccttgca atcccgagaa ctgttgattg gtgtgtggtc 52860 agtcaatgta cacagaaact cctccaatca aagaaagaaa caagtgagaa ttcttaaata 52920 gtgggtattt caaaagtaac ttctatagaa ctattatttc ctgtgacttt ttctttactg 52980 atttctgatt tacttactga tttccaacaa actaagaaat gtgtccaaga aggacttatg 53040 catatatgtt atttttacca tgatcccatg cttgttcatt tctttttata gacattagaa 53100 aaaaatcaaa gatgggtttt tgttgtcaac taagaccaca attgggagtg ttaaagttat 53160 aatttttaaa aaccgagaca attgaatata ctacttggat ttaatttttt ttaagcataa 53220 tttgggaaga atgtaaatta tttcaatttt ccacttctta ttgctggata acaaatagaa 53280 tgtatgcaac agtgaagact ctagtttgat cttatataga ttgaggaatt cgtaggaaca 53340 aaccatgctg tttctggtct aggattttac tgagctgcat agaacttaag aacatggcat 53400 cagaagcagg tcagccagca atcccagtgc tctcagtgac tttgggaaga cagtttcttc 53460 tttggtgtca agtgtgttca gctttgcagc aagggcaggg cctgcctttg agatgcctct 53520 gtaaatggaa ttttactttt tcttcagtcc ttggagaact gatgtgtttg cttactggct 53580 tttaaaactt ggcccccaac ttttctcttt atatgtattg gggtggaggg ggaaattcaa 53640 agggccggtg tctctttgtt cttacccaag cccacaatta gttgatgttt ctgctgtgta 53700 gctggagggg aagggagggg tgggccagca gtcttttact gcctctgaga aagtgttctg 53760 ctggctcctt tgtccttttt gtcagggacc actgcctccc taattgtcct gatgtaggga 53820 agcacgcgcc cttgccagca ttatctgatt tctacaggac gtccaagagt actttgtata 53880 ctgaccctta aggaaacaca aataaggttt cttcaatccc cttcccaagc tgtggccccc 53940 cagcttgcta cctaagagct ttagtttagc agaatgtaga cacattttta cctgcctctg 54000 gttgtgtgtg tgttttttcc cctgctgctc acattgtcta cctgtagttt agccacaccc 54060 gtctggaagg gaggtcgagg atgaagggta ggtaggagag gggtaggcac tgtaaaagtc 54120 agaagggaga gaagacggga caaacagctg cacttgtcaa catggggata agtgtaaata 54180 gattaatagt tatttacaga gcaaatggga ggtagcattc agcagtggaa tgtgagtgcc 54240 tgaatggaat gggctgggtg tgcggctgtg cgcattgcag cagatgctct ctggcctgaa 54300 tggaatgact gagtccgttt atcttctcct gagacagagt taagatggac aaaatcatgc 54360 tattaaattc aaagtttaaa atgaaaagca aaaattcaag ccctctctct ccctctctct 54420 ctttctctct ctctctctct ctctctctcc ttcttccttt atttccttcc tttttttctt 54480 ttctgttttc tttttttaaa tcatttttat gcttcattat tttccatagc ctgagtcttt 54540 cgggattata tttctatgga aaaattagcc tccttacctc ctttttaaaa aatgtaccaa 54600 caggaatgag tctgttcccc ttcattagct ggaagagaaa ccaaggctgc catggctcaa 54660 aaaaattgcc atcaagagaa acagaaccaa aggctggtga gccctctgga aacaggctca 54720 atgtgactct aattaagggg caactgacag tcactgtcag aggacttagg cagtttcaga 54780 agttctagtc catccaaggg gtaaattatt tttccttctc tgattatgag aaagttgttt 54840 ttcaggtaaa taggcagatt ttgatgaatt tcataatcat ctagtgcaaa ccaactctgt 54900 gcttgggagc tacaagaact atcaagtatt tctgaattat gtccacctca atatttattt 54960 atttatttat ttatttattt atttatttat ttatctattt atttaggttt ttgagacagg 55020 atttctctgt gtagtcctgg ctatcctggc actagctcta tagaccaggt tggcctggaa 55080 ctcataggat ctgtctgcct ccacctacca aatgctggga ttaaaggcat gtgccaccac 55140 gcccagctcc accacagaat tttatctcta gctaacagat gtagagtaca gattcttcaa 55200 aattagagct ggatggcatg ctagtattgt gggttacctt gcattgcatg tggtaaagct 55260 gaccgtggtg gttcaggcct atgagcccta gctcctctgg agaaaaaggc aggaggatgg 55320 cgaaagcgag tttgaatcta atctgagaag caaacaaaat atcatctcag aaaagaaagt 55380 tcgtggtggc atttccctaa ccatgctccc catttcaccc tagtcatttc aagcttgttc 55440 ccagaatgat caactgtcac ataaatttag atgtaatgct ataaagaaat tttgccttat 55500 gtgtgcaacc atttgatact caactctcat aaacctatca gttgctctct ttgcttatga 55560 atattgtagc aacgtgagag ctagagtgag gtggcttctt cttcttcttc ttcttcttct 55620 tcttcttctt cttcttcttc ttcttcttct tcttcttctt cttcttcttt ttcttcttct 55680 tctccttctc cttcttcttt ctcttcctcc tcctccttct cctcctcttc ttcttctact 55740 agtactacta ctgctactac ttcctattcc tccttctctt tttcttcctc ttccttctcc 55800 ttcccttcct cctcttcttc ctctccctct ttttttctcc tcttcctctt cttcctcccc 55860 ttcttttttc ttcttcctct tcctcctcca ctcttttctc cttctccttc ctcttcctcc 55920 tcttcctcct tcttcaagaa gtaatacaga aagtatttaa agtaattctc agcagtgtca 55980 tgccctgagc acattgtacc tgttttgagt gtgtactcta ttttccaaca atcacacagt 56040 tgcactgggt gtttccttct accacagatg ggtggcttta cttgggacat gacgtgtttg 56 100 ggacatcatg cccaaatttt tacaaagcac accaaataat gccaatttta ttgagcaatg 56160 aactgtggct tgcatgacta atgttggggt gtctggatgt ctttacagcc acagtacacg 56220 aacctggggc tcctgaacag catggaccag cagattcaga acggctcctc gtccaccagc 56280 ccctacaaca cagaccacgc acagaatagc gtgacggcgc cctcgcccta tgcacagccc 56340 agctccacct ttgatgccct ctctccatcc cctgccattc cctccaacac agatta 56396 <210> 2 <211> 49 <212> DNA <213> Artificial Sequence <220> <223> Forward arm sequence in ET-recombination <400> 2 tgccctctct ccatcccctg ccattccctc caacacagat tacccgggc 49 <210> 3 <211> 49 <212> DNA <213> Artificial Sequence <220> Reverse arm sequence in ET-recombination <400> 3 gcccagaaac catattgttt tgttaaatat tatttggtga tgtctagga 49

Claims (7)

DNp63 promoter, characterized by inducing expression of DNp63 protein in contact with a potential anticancer agent in epithelial cell derived cancer cells. The DNp63 promoter according to claim 1, wherein the promoter is SEQ ID NO: 1. Recombinant vector for screening an anticancer agent, characterized in that it comprises a reporter gene for confirming expression with the promoter of claim 1. 4. The recombinant vector for screening anticancer agents according to claim 3, wherein the reporter gene is a green fluorescent protein (GFP). Cancer cells for screening anticancer agent transformed with the recombinant vector according to claim 3. Transforming the recombinant vector according to claim 3 into epithelial-derived cancer cells; Contacting the potential anticancer substance with the cancer cell; Anticancer substance screening method comprising the step of measuring the expression amount of the reporter in the cancer cells. Epithelial-derived cancer cells transformed with the recombinant vector according to claim 3; Means for contacting a potential anticancer substance with the cancer cell; And Anti-cancer agent diagnostic kit, characterized in that it comprises a means for measuring the expression level of green fluorescent protein in the cancer cells.

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