KR101789877B1 - Lytic bacteriophage specific for Pseudomonas genus resistant to antibiotics - Google Patents

Lytic bacteriophage specific for Pseudomonas genus resistant to antibiotics Download PDF

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KR101789877B1
KR101789877B1 KR1020150138711A KR20150138711A KR101789877B1 KR 101789877 B1 KR101789877 B1 KR 101789877B1 KR 1020150138711 A KR1020150138711 A KR 1020150138711A KR 20150138711 A KR20150138711 A KR 20150138711A KR 101789877 B1 KR101789877 B1 KR 101789877B1
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용동은
전종수
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Abstract

본 발명은 강력한 항균제인 카바페넴(carbapenem)에 대한 내성을 보이는 슈도모나스 균속을 용균시키는 박테리오파지 YMC11/02/R656 PAE BP [KCTC18363P]에 관한 것이다.
본 발명에서 제공하는 신규한 박테리오파지는 강력한 항균제인 카바페넴 내성 슈도모나스 균속에 대하여 특이적 사멸능을 가지므로, 상기한 카바페넴 내성 슈도모나스 균속에 의해 유발되는 질환의 예방 및 치료 목적으로 활용할 수 있다. The present invention relates to bacteriophage YMC11 / 02 / R656 PAE BP [KCTC18363P] which lyses Pseudomonas sp. Showing resistance to carbapenem, a potent antimicrobial agent.
The novel bacteriophage provided in the present invention has a specific killing activity against carbapenem-resistant Pseudomonas sp., A potent antimicrobial agent, and thus can be utilized for the prevention and treatment of diseases caused by carbapenem-resistant Pseudomonas sp.

Description

항생제 내성을 갖는 슈도모나스 균속을 용균하는 박테리오파지{Lytic bacteriophage specific for Pseudomonas genus resistant to antibiotics}BACKGROUND OF THE INVENTION 1. Field of the Invention [0001] The present invention relates to a bacteriophage that lyses Pseudomonas sp. Having antibiotic resistance.

본 발명은 항균제 중에서도 특히 카바페넴(carbapenem)에 대한 내성을 보이는 슈도모나스 균속을 용균시키는 박테리오파지에 관한 것이다.The present invention relates to a bacteriophage which lyses Pseudomonas sp., Particularly showing resistance to carbapenem among antimicrobial agents.

녹농균(Pseudomonas aeruginosa)은 그람 음성 간균으로 포도당 비발효 세균이다. 이들은 토양, 물, 하수 등을 포함한 자연환경, 사람의 피부, 구강, 호흡기계 점막 등에 상재균으로 분포한다. 이들 세균은 신생아, 비장 절제술 시행 환자, 장기간 스테로이드를 투여한 환자, 항암 치료 중인 암환자, 장기 이식 환자, 집중치료실 환자와 같은 면역력이 저하된 고위험군 환자에서의 내인성 기회감염을 일으키는 중요한 병원성 세균이다 [비특허문헌 1]. Pseudomonas aeruginosa is a gram negative bacillus and is a glucose non-fermenting bacterium. They are distributed in the natural environment including soil, water, sewage, etc., human skin, oral cavity, and respiratory mucosa. These bacteria are important pathogenic bacteria causing endogenous opportunistic infections in newborn infants, spleen resection patients, long-term steroids, cancer patients undergoing chemotherapy, organ transplant patients, and immunocompromised high-risk patients such as intensive care unit patients [ Non-Patent Document 1].

녹농균이 일으키는 원내 감염증으로는 폐렴, 화상 환자에서의 감염, 뇌수막염, 심내막염 및 균혈증 등이 있고, 인공호흡기, 혈관 내 침습적 조작술, 침구류 및 의료진의 손을 통한 원내 집단 발병이 보고되고 있다 [비특허문헌 2]. 특히, 항암 치료 등으로 인한 면역저하 환자가 증가하고 있는 환경에서 녹농균 감염은 호흡기에서 30 내지 60%, 패혈증에서 80 내지 100%의 높은 사망률을 보임이 보고되어 있다. Pseudomonas infections caused by P. aeruginosa include pneumonia, infection in burn patients, meningitis, endocarditis and bacteremia, and there have been reports of onset of intracranial masses through the hands of respirators, intravascular invasive procedures, bed linen, and medical staff Literature 2]. In particular, it has been reported that Pseudomonas aeruginosa infection has a high mortality rate of 30 to 60% in the respiratory tract and 80 to 100% in the sepsis case in the environment where the immunocompromised patients due to the chemotherapy and the like are increasing.

이들의 국내 분리 빈도는 2007년 7월부터 9월까지 세브란스 병원 자료에 의하면 녹농균 1,114주가 분리되어 가장 빈번한 병원균이었다 (항균제 내성 소식지 59호, www.whonet.org). 2004년 국내 44개 병원 검사실과 1개 지역사회 검사실이 참여한 KONSAR 그룹의 조사 자료에 의하면 Pseudomonas가 전체 원내 분리 병원균 중 Staphylococcusaureus (20.2%), Escherichiacoli(17.7%)에 이어 13.3%가 분리되어 3번째로 흔하였다 [비특허문헌 3].From July to September 2007, according to the data from Severance Hospital, 1,114 pseudomonas aeruginosa isolates were the most frequent pathogens (Antimicrobial Resistance News No.59, www.whonet.org). According to the survey data of KONSAR group which participated in 44 domestic hospitals and one community laboratory in 2004, 13.3% of Pseudomonas isolates were followed by Staphylococcus aureus (20.2%) and Escherichia coli (17.7%) [Non-Patent Document 3].

한편, 카바페넴(carbapenem)은 그 항균 범위가 가장 넓고, ESBL이나 AmpC β-락타마제를 포함한 클래스 A, D 및 D β-락타마제에 안정한 가장 강력한 β-락탐 항균제에 해당한다. 그런데 현재 국내뿐만 아니라 세계적으로 카바페넴(carbapenem) 제제조차 내성을 보이는 다제 내성(multidrug resistant) 녹농균에 의한 감염이 증가하고 있어서 임상적으로 커다란 문제가 되고 있다. Carbapenem, on the other hand, has the broadest antimicrobial range and is the most potent β-lactam antibiotic stable to Class A, D and D β-lactamase, including ESBL and AmpC β-lactamase. However, there is a growing clinical problem because of the increased infection by multidrug resistant Pseudomonas aeruginosa resistant to carbapenem drugs both domestically and globally.

감염증 환자를 감수성을 보이는 항생제로 적절한 치료를 하는 경우 약 90%의 양호한 예후를 기대할 수 있고, 내성을 보이는 항생제로 치료하는 경우는 약 60% 밖에 반응하지 않았다. 이들 세균에 사용할 수 있는 약제는 콜리스틴(colistin), 티제사이클린(tigecyclin)이 남아 있는 실정이나 약제의 부작용 혹은 고가로 인해 그 사용에 어려움이 많다. 더군다나 새로운 항생제 개발이 이미 한계에 도달하고 있으므로 앞으로도 개선의 여지는 매우 적다고 사료된다. 이로써 판단하여 볼 때 항생제 내성 세균의 증가는 광범위한 침습적 시술, 항암 요법, 장기이식 등으로 면역저하 환자가 필연적으로 발생하는 현대 의학의 근간을 흔드는 심각한 문제라고 판단된다. Approximately 90% of patients with infectious disease susceptibility to antibiotics are expected to have a good prognosis, and only 60% of patients with resistant antibiotics have responded. The drugs that can be used for these bacteria are colistin and tigecycline, but they are difficult to use because of side effects or high price of drugs. Furthermore, since the development of new antibiotics has already reached its limit, there is little room for improvement in the future. Based on these results, it is considered that the increase of antibiotic resistant bacteria is a serious problem that paves the foundation of modern medicine in which immune compromised patients necessarily arise due to extensive invasive procedures, chemotherapy and organ transplantation.

과거 1960년대와 1970년대 초반까지 항생제 개발에 괄목할 만한 많은 성과가 있었고, 이를 통하여 많은 감염증이 치료되었다. 그러나 40 여년이 지나고 있는 요즈음 감염병은 전세계적으로 2번째 흔한 사인이자 [비특허문헌 4], 미국 내에서는 3번째 사인으로 보고되어서 [비특허문헌 5] 그 심각성이 줄어들지 않고 있다. 더군다나 최근 여러 항생제에 내성인 세균이 출현, 증가하고 있어서 약제 선택의 폭이 현저히 줄어들고 있는 실정이다.Until the 1960s and early 1970s, there have been remarkable achievements in the development of antibiotics, and many infections have been treated. However, in recent 40 years, infectious diseases have been reported to be the second most common cause worldwide [Non-Patent Document 4] and the third in the United States [Non-Patent Document 5]. Furthermore, the number of antibiotic-resistant bacteria has been increasing and the number of medicines has been greatly reduced.

비록 항생제가 박테리아에 의한 감염성 질환의 치료에 있어 여전히 주된 방법으로 널리 사용되고 있는 실정이지만, 과도한 항생제의 사용으로 인하여 1980년대부터 많은 항생제 내성 균주가 발생하기 시작했으며 상기 예시된 바와 같이 더 이상 기존 항생제로는 효과적 치료를 기대할 수 없는 일명 슈퍼박테리아(super-bacteria) 또는 슈퍼버그(super-bug)라 불리는 내성균(resistant bacteria)까지 발생하여 사회적으로 크나큰 문제로 대두되고 있다. 이런 이유로 기존 항생제에 대하여 내성을 획득한 박테리아에 의한 질환까지도 치료할 수 있는 새로운 항생 물질의 개발이 시급하다 할 수 있다.Although antibiotics are still widely used as a main method in the treatment of infectious diseases caused by bacteria, many antibiotic resistant strains have been started to develop from the 1980s due to excessive use of antibiotics. As shown above, Has emerged as a socially major problem because of the occurrence of resistant bacteria called super-bacteria or super-bugs, which can not be expected to be treated effectively. For this reason, it is urgent to develop new antibiotics that can treat diseases caused by bacteria that have acquired tolerance to existing antibiotics.

이처럼 내성균이 증가하게 된 주된 원인으로는 무분별한 항생제 오남용(mis- and over-use)으로 인한 사람, 가축, 야생동물, 양식어류, 토양, 하천, 바다 등 환경 전체의 항생제 오염을 들 수 있다. 항생제 과다 사용이 새롭게 개발된 항생제에 대한 박테리아의 내성 획득 시간을 과거보다 더 짧게 만드는 하나의 원인이 되고 있는 것이다. 그러나 보다 더 근본적인 원인은 새롭게 개발된 합성 항생제 대부분이 과거 개발된 항생제의 기본 골격 구조를 그대로 유지하면서 화학적으로 약간의 구조만을 변경시키는 방식으로 개발되고 있는 기술적 한계에 크게 기인하고 있다고 할 수 있다. 현재 시장에 나와 있는 모든 항생제는 내성 문제에 직면하고 있으며, 이에 따라 기존 항생제의 내성 문제에서 자유로운 새로운 계열(class)의 항생제의 개발에 대한 요구가 큰 실정이다. 그럼에도 불구하고 지난 50년 동안 발견된 새로운 항생제 계열은 옥사졸리디논(Oxazolidinones), 고리형 리포펩타이드(cyclic lipopeptides), 프라텐시마이신(platensimycin)의 3 가지뿐이다. 따라서 새로운 항생제 계열에 대한 요구는 여전하다고 할 수 있으며, 이들 새로운 항생제는 현재 일반적으로 사용되는 항생제에 대하여 내성이 생긴 박테리아에도 항균 활성이 있어야 할 것이다.The main reason for the increase in the number of resistant bacteria is antibiotic contamination of whole environment such as human, livestock, wild animals, aquaculture, soil, river and sea due to irrelevant antibiotic mis- and over-use. The overuse of antibiotics is one of the reasons to make bacterial resistance acquisition time of newly developed antibiotics shorter than in the past. However, the more fundamental cause is that most newly developed synthetic antibiotics are largely due to technological limitations that are developed in such a way that only the structure of the antibiotics is modified chemically while maintaining the basic skeletal structure of the previously developed antibiotics. All current antibiotics on the market face resistance problems, and there is a great demand for the development of new class of antibiotics free from the problem of resistance to existing antibiotics. Nevertheless, there are only three new classes of antibiotics discovered over the last 50 years: oxazolidinones, cyclic lipopeptides, and platensimycin. Therefore, the demand for new antibiotics is still present, and these new antibiotics should have antimicrobial activity against bacteria that are resistant to commonly used antibiotics.

항생제 오남용 및 이로 인한 내성균 출현 등으로 대표되는 기존 합성 항생제의 문제점이 세계적으로 크게 이슈화되어 있는 상황에서 이에 대한 해결책을 제시해 줄 수 있는 대상으로 주목을 받고 있는 것이 바로 박테리오파지(Bacteriophage) 및 박테리오파지 유래의 리신(Lysin) 단백질이다. 박테리오파지 및 리신 단백질은 기존 항생 물질과는 완전히 다른 계열이라 할 수 있으며 이에 따라 전혀 다른 항균(antibacterial) 작용 기작(mode of action)을 갖고 있다. 따라서 기존 항생제의 사용에서 나타나던 여러 부작용(side effect)이나 문제점을 개선할 수 있을 것으로 기대를 모으고 있다.The problem of existing synthetic antibiotics such as abuse of antibiotics and the emergence of resistant bacteria caused by the antibiotics has been a major issue in the world, and it has been attracting attention as a possible solution for this problem. Bacteriophages and bacteriophage-derived lysine (Lysin) protein. Bacteriophages and lysine proteins are completely different from existing antibiotics and thus have completely different antibacterial mode of action. Therefore, it is anticipated that it will be possible to improve various side effects or problems in the use of existing antibiotics.

박테리오파지는 박테리아를 감염시킬 수 있으며 보통 파지(phage)라고 줄여서 부르기도 한다. 박테리오파지는 핵산으로 이루어진 유전물질 중심부를 단백질 외피가 싸고 있는 단순한 구조의 유기체이며, 핵산은 단일 사슬이거나 이중 사슬인 DNA 또는 RNA로 되어있다. 박테리오파지는 생존에 숙주(host)가 반드시 필요하며, 모든 박테리아에는 특정 박테리오파지가 존재한다고 알려져 있다. 박테리오파지는 박테리아의 세포벽(cell wall)의 펩티도글리칸(peptidoglycan) 층(layer)을 공격하여 세포벽을 파괴함으로써 박테리아를 사멸시킬 수 있다. 박테리오파지는 1915년 영국의 세균학자 Twort와 1917년 프랑스의 d’Herelle에 의해 독립적으로 규명되었으며 세균을 잡아먹는다는 뜻에서 박테리오파지라고 명명되었다. 박테리오파지의 항박테리아 활성(antibacterial activity) 때문에 발견 직후부터 인체와 동물의 질병 치료에 사용되었다. 그러나 Flemming에 의해 페니실린이 발견된 이후, 계속된 다양한 항생제의 등장 및 보급화로 인하여 서구에서는 관심이 점차 줄어들게 되었다. 그러나 러시아와 독일 등의 동구권 나라들은 박테리오파지 연구를 계속 해왔으며 관련하여 다수의 제품들이 산업화된 바도 있다. 하지만, 2000년대에 이르러 항생제 내성균 문제가 부각되면서 서구에서도 다시 박테리오파지에 대하여 관심을 갖게 되었으며 그 후 약 7 ~ 8년이 흐른 최근, 산업화 사례들이 속속 보고되고 있다. 즉, 박테리오파지가 세계적으로 새롭게 재조명되기 시작한 시기는 2000년대 초반으로, 실질적 산업화 노력이 약 7 ~ 8여년 정도 진행된 신규한 분야로서, 생명공학기술의 발전과 맞물려 최근 매우 활발히 관련 개발이 진행되고 있는 분야라 할 수 있다.Bacteriophages can infect bacteria and are often called phages. A bacteriophage is a simple structure organism with a protein envelope wrapped around a nucleus of genetic material, and the nucleic acid is a single chain or double-stranded DNA or RNA. A bacteriophage is a host that is required to survive, and all bacteria are known to have certain bacteriophages. Bacteriophages can kill bacteria by attacking the peptidoglycan layer of the cell wall of bacteria and destroying the cell walls. The bacteriophage was identified independently by the British germologist Twort in 1915 and d'Herelle in France in 1917 and was named bacteriophage in the sense that it eats bacteria. Because of the antibacterial activity of bacteriophage, it was used for the treatment of diseases of humans and animals immediately after its discovery. However, since the discovery of penicillin by Flemming, interest in the West has gradually diminished due to the continued emergence and dissemination of various antibiotics. However, the Eastern bloc countries such as Russia and Germany have continued to study bacteriophage, and many products have been industrialized. However, as the problem of antibiotic-resistant bacteria has emerged in the 2000s, the bacteriophage became interested in the bacteriophage again in the West. Recently, industrialization cases have been reported about 7 ~ 8 years later. In other words, bacteriophage began to be reemerged in the world in the early 2000s, and it is a new field where practical industrialization efforts have been carried out for about 7 to 8 years. In the field of biotechnology, .

박테리오파지의 가장 큰 특징으로는, 감염성 박테리아 속에 침투한 다음 박테리아의 세포벽을 파괴하여 박테리아의 사멸을 유도한다는 것이며, 이러한 박테리오파지에 의한 세포 사멸의 기작은 세균의 세포벽 합성을 방해하는 방식의 기존 합성 항생제의 기작과는 완전히 다르다. 따라서 기존 합성 항생제에 대한 감수성에 관계 없이 자신의 항균 활성을 발휘할 수 있다. 이로 인하여 특히 기존 항생제에 대하여 이미 내성을 획득한 내성균에 대해서도 항균 효과가 있다. 또한, 박테리아에 대해서는 매우 특이적인 항균 활성을 가지고 있기 때문에 인간을 포함한 동물을 구성하는 세포인 진핵세포(eukaryotic cell)에는 영향을 주지 않는다는 장점을 갖고 있다.The major feature of bacteriophage is that it penetrates into infectious bacteria and then destroys the cell walls of the bacteria to induce the death of the bacteria. The mechanism of this cell death by bacteriophage is that of existing synthetic antibiotics It is completely different from the mechanism. Therefore, it can exert its antimicrobial activity irrespective of susceptibility to existing synthetic antibiotics. Therefore, it has an antibacterial effect against resistant bacteria that have already acquired tolerance to existing antibiotics. In addition, it has an advantage that it does not affect eukaryotic cells, which constitute animals including humans, because they have a very specific antibacterial activity against bacteria.

Patrick PR, et al. eds. Manual of Clinical Microbiology. 8th eds. ASM press. 2003Patrick PR, et al. eds. Manual of Clinical Microbiology. 8th eds. ASM press. 2003 Spencer RC. Predominant pathogens found in the European Prevalence of Infection in Intensive Care Study. Eur J Clin Microbiol Infect Dis 1996; 15: 281-5.Spencer RC. Predominant pathogens found in the European Prevalence of Infection in Intensive Care Study. Eur J Clin Microbiol Infect Dis 1996; 15: 281-5. Lee K. et al. High prevalence of ceftazidime-resistant Klebsiella pneumoniae and increase of imipenem-resistant Pseudomonas aeruginosa and Acinetobacter spp. in Korea: a KONSAR program in 2004. Yonsei Med Journal 2006;47:634Lee K. et al. High prevalence of ceftazidime-resistant Klebsiella pneumoniae and an increase in imipenem-resistant Pseudomonas aeruginosa and Acinetobacter spp. in Korea: a KONSAR program in 2004. Yonsei Med Journal 2006; 47: 634 WHO. World Health Report-2002. Geneva: 2002WHO. World Health Report-2002. Geneva: 2002 Pinner RW. Trends in infectious diseases mortality in the United States. JAMA. 1996:275:189Pinner RW. Trends in infectious diseases in the United States. JAMA. 1996: 275: 189

본 발명의 일 목적은 카바페넴 내성 슈도모나스 균속에 대한 특이적 감염 및 사멸능을 갖는 신규한 박테리오파지를 제공하는 것이다.It is an object of the present invention to provide a novel bacteriophage having a specific infectious and killing ability against carbapenem-resistant Pseudomonas spp.

본 발명의 다른 목적은 카바페넴 내성 슈도모나스 균속에 대한 특이적 감염 및 사멸능을 갖는 신규한 박테리오파지에 의해 유발되는 질환의 예방 및 치료용 조성물과 질환 개선용 식품 조성물을 제공하는 것이다.Another object of the present invention is to provide a composition for the prevention and treatment of diseases caused by a novel bacteriophage having a specific infectious and killing activity against carbapenem-resistant Pseudomonas sp. And a food composition for improving disease.

본 발명의 발명자들은 카바페넴 내성 세균 감염증 치료의 대안 물질로 기존의 화학용법 제제를 보완할 수 있는 박테리오파지를 검토하던 중 카바페넴 내성 녹농균(Pseudomonas aeruginosa)을 선택적으로 사멸시킬 수 있는 박테리오파지를 분리하고, 분리된 박테리오파지의 형태적 및 유전적 특성을 분석하여 이를 타 박테리오파지와 구별하여 특정 지을 수 있는 유전체(genome)의 유전자 서열을 제공하며, 더 나아가 카바페넴 내성 녹농균 특이적 사멸능을 갖는 분리된 박테리오파지를 이용하여 카바페넴 내성 녹농균에 의해 유발되는 질환의 예방 및 치료 목적으로 이용함으로써 본 발명을 완성하였다.The inventors of the present invention have investigated bacteriophages that can complement the conventional chemotherapeutic agents as an alternative to carbapenem resistant bacterium infection. Bacteriophages capable of selectively killing carbapenem resistant pseudomonas aeruginosa were isolated, By analyzing the morphological and genetic characteristics of the isolated bacteriophage, it is possible to distinguish it from other bacteriophages and provide a gene sequence of a specific genome. Further, it is possible to isolate bacteriophages having a carbapenem-resistant P. aeruginosa- For the prevention and treatment of diseases caused by carbapenem-resistant P. aeruginosa.

구체적으로, 본 발명자들은 카바페넴 내성 녹농균을 선택적으로 사멸시키기 위해 예의 노력한 결과, 병원체로부터 녹농균을 분리하고 이 녹농균을 특이적으로 사멸시킬 수 있는 신규한 박테리오파지를 선별하였고, 이를 YMC11/02/R656 PAE BP로 명명하였다. 이렇게 선별된 박테리오파지 YMC11/02/R656 PAE BP를 2015년 3월 23일자로 한국생명공학연구원 미생물자원센터 (기탁번호 KCTC18363P)에 기탁하였다. Specifically, the present inventors have made intensive efforts to selectively kill cabbagepenem resistant P. aeruginosa, and as a result, they have isolated novel P. aeruginosa from pathogens and selected novel bacteriophages capable of specifically killing the P. aeruginosa. The present inventors selected YMC11 / 02 / R656 PAE BP. The selected bacteriophage YMC11 / 02 / R656 PAE BP was deposited on March 23, 2015 with the Center for Microbial Resources, Korea Research Institute of Bioscience and Biotechnology (Accession No. KCTC18363P).

본 발명의 일 구현 예에 따르면 항생제 내성 슈도모나스 균속에 대하여 선별된 박테리오파지는 서열번호 2 내지 12 중 적어도 하나로 표시되는 유전체를 포함할 수 있다. According to an embodiment of the present invention, the bacteriophage selected for the antibiotic-resistant Pseudomonas sp. May comprise a dielectric represented by at least one of SEQ ID NOS: 2 to 12.

본 발명에서 상기 박테리오파지의 유전체의 핵산 분자 서열을 제공한다 (서열번호 1).In the present invention, a nucleic acid molecule sequence of the genome of the bacteriophage is provided (SEQ ID NO: 1).

본 발명에서 상기 항생제 내성 슈도모나스 균속에 속하는 균종은 녹농균(Pseudomonas aeruginosa)일 수 있다.In the present invention, the microorganism belonging to the antibiotic-resistant Pseudomonas sp. Can be Pseudomonas aeruginosa.

본 발명에서 상기 항생제는 카바페넴일 수 있고, 상기 항생제 내성 슈도모나스 균속이 생산하는 효소는 카바페넴아제일 수 있다. In the present invention, the antibiotic may be carbapenem, and the enzyme produced by the antibiotic-resistant Pseudomonas sp. May be carbapenemase.

본 명세서에서 사용된 "핵산 분자"라는 용어는 DNA (gDNA 및 cDNA) 그리고 RNA 분자를 포괄적으로 포함하는 의미를 가지며, 핵산 분자에서 기본 구성 단위인 뉴클레오타이드는 자연의 뉴클레오타이드 뿐만 아니라, 당 또는 염기 부위가 변형된 유사체(analogue)도 포함한다(Scheit, Nucleotide Analogs, John Wiley, New York(1980); Uhlman 및 Peyman, Chemical Reviews, 90:543-584(1990)).As used herein, the term "nucleic acid molecule" is intended to encompass both DNA (gDNA and cDNA) and RNA molecules, and the nucleotide, which is a basic constituent unit in the nucleic acid molecule, includes not only natural nucleotides, Also included are modified analogues (Scheit, Nucleotide Analogs, John Wiley, New York (1980); Uhlman and Peyman, Chemical Reviews, 90: 543-584 (1990)).

본 발명의 다른 구현 예에 따르면, 항생제 내성 슈도모나스 균속에 의해 유발되는 질환의 예방 또는 치료용으로서 박테리오파지 YMC11/02/R656 PAE BP [KCTC18363P]를 유효성분으로 포함하는 약학적 조성물을 제공한다.According to another embodiment of the present invention, there is provided a pharmaceutical composition comprising, as an active ingredient, bacteriophage YMC11 / 02 / R656 PAE BP [KCTC18363P] for the prevention or treatment of diseases caused by antibiotic resistant Pseudomonas sp.

본 발명의 약학적 조성물은 1 × 103 내지 1 × 1010 pfu/㎖의 박테리오파지를 포함하며, 바람직하게는 1 × 106 내지 1 × 109 pfu/㎖의 박테리오파지를 포함할 수 있다. The pharmaceutical composition of the present invention comprises 1 × 10 3 to 1 × 10 10 pfu / ml of bacteriophage, preferably 1 × 10 6 to 1 × 10 9 pfu / ml of bacteriophage.

본 발명의 약학적 조성물에 포함되는 박테리오파지 YMC11/02/R656 PAE BP [KCTC18363P]는 상술한 바와 같이, 항생제 내성 슈도모나스 균속, 바람직하게는 카바페넴 내성 녹농균을 특이적으로 사멸시키므로, 녹농균에 의해 유발되는 다양한 질환의 치료에 효과를 나타낸다.As described above, the bacteriophage YMC11 / 02 / R656 PAE BP [KCTC18363P] contained in the pharmaceutical composition of the present invention specifically kills antibiotic-resistant Pseudomonas spp., Preferably carbapenem-resistant P. aeruginosa, It is effective in the treatment of various diseases.

녹농균은 폐렴, 뇌수막염, 균혈증, 심내막염 및 내인성 기회감염 등을 일으키는 원인균으로서, 본 발명의 약학적 조성물은 녹농균에 의해 유발되는 다양한 질환(녹농균 유발성 질환), 예컨대 폐렴, 뇌수막염, 균혈증, 심내막염 및 내인성 기회감염 등에 대한 치료에 이용될 수 있다. Pseudomonas aeruginosa is a causative organism causing pneumonia, meningitis, bacteremia, endocarditis and endogenous opportunistic infection. The pharmaceutical composition of the present invention is useful as a medicament for treating various diseases (Pseudomonas spp.) Caused by P. aeruginosa such as pneumonia, meningitis, bacteremia, Opportunistic infections, and the like.

본 명세서에서 사용된 '치료'라는 용어는 (ⅰ) 녹농균에 의해 유발된 질환의 예방; (ⅱ) 녹농균에 의해 유발된 질환의 억제; 및 (ⅲ) 녹농균에 의해 유발된 질환의 경감을 의미한다.As used herein, the term ' treatment ' refers to (i) prevention of diseases caused by P. aeruginosa; (Ii) inhibition of diseases caused by P. aeruginosa; And (iii) alleviating the disease caused by P. aeruginosa.

또한, 본 발명에서 상기 약학적 조성물은 통상의 방법에 따른 적절한 담체, 부형제 또는 희석제를 추가로 포함할 수 있다. 본 발명의 약학적 조성물에 포함될 수 있는 담체, 부형제 및 희석제로는 락토즈, 덱스트로즈, 수크로스, 솔비톨, 만니톨, 자일리톨, 에리스리톨, 말티톨, 전분, 아카시아 고무, 알지네이트, 젤라틴, 칼슘 포스페이트, 칼슘 실리케이트, 셀룰로즈, 메틸 셀룰로즈, 미정질 셀룰로스, 폴리비닐 피롤리돈, 메틸히드록시 벤조에이트, 프로필히드록시벤조에이트, 탈크, 마그네슘 스테아레이트 및 광물유 등을 사용할 수 있으나, 이에 제한되지 않는다. In addition, in the present invention, the pharmaceutical composition may further comprise an appropriate carrier, excipient or diluent according to a conventional method. Examples of carriers, excipients and diluents that can be included in the pharmaceutical composition of the present invention include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, acacia rubber, alginate, gelatin, calcium phosphate, calcium But are not limited to, silicates, cellulose, methylcellulose, microcrystalline cellulose, polyvinylpyrrolidone, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate and mineral oil.

또한, 본 발명에 따른 약학적 조성물은, 각각 통상의 방법에 따라 산제, 과립제, 정제, 캡슐제, 현탁액, 에멀젼, 시럽, 에어로졸 등의 경구형 제형, 외용제, 좌제 또는 멸균 주사용액의 형태로 제형화하여 사용될 수 있다. 상세하게는, 제제화할 경우에는 보통 사용하는 충진제, 증량제, 결합제, 습윤제, 붕해제, 계면활성제 등의 희석제 또는 부형제를 사용하여 조제될 수 있다. 경구 투여를 위한 고형제제에는 정제, 환제, 산제, 과립제, 캡슐제 등이 포함되며, 이러한 고형제제는 상기 본 발명의 약학적 조성물에 적어도 하나 이상의 부형제 예를 들면, 전분, 칼슘카보네이트 (calcium carbonate), 수크로스 (sucrose), 락토오스 (lactose), 젤라틴 등을 섞어 조제될 수 있다. 또한, 단순한 부형제 이외에 마그네슘 스테아레이트, 탈크 같은 윤활제들도 사용될 수 있다. 경구를 위한 액상 제제로는 현탁제, 내용액제, 유제, 시럽제 등이 해당되는 데, 흔히 사용되는 단순 희석제인 물, 리퀴드 파라핀 이외에 여러 가지 부형제, 예를 들면 습윤제, 감미제, 방향제, 보존제 등이 포함될 수 있다. 비경구 투여를 위한 제제에는 멸균된 수용액, 비수성용제, 현탁제, 유제, 동결건조 제제 및 좌제가 포함된다. 비수성용제, 현탁제로는 프로필렌글리콜 (propylene glycol), 폴리에틸렌 글리콜, 올리브 오일과 같은 식물성 기름, 에틸올레이트와 같은 주사 가능한 에스테르 등이 사용될 수 있다. 좌제의 기제로는 위텝솔 (witepsol), 마크로골, 트윈 (tween) 61, 카카오지, 라우린지, 글리세로젤라틴 등이 사용될 수 있다. The pharmaceutical composition according to the present invention may be formulated in the form of powders, granules, tablets, capsules, suspensions, emulsions, syrups, aerosols and the like, external preparations, suppositories or sterilized injection solutions, Can be used. More specifically, when formulating the composition, it can be prepared using a diluent or an excipient such as a filler, an extender, a binder, a wetting agent, a disintegrant, a surfactant, and the like. The solid preparations for oral administration include tablets, pills, powders, granules, capsules and the like. These solid preparations can be prepared by mixing at least one excipient such as starch, calcium carbonate, Sucrose, lactose, gelatin, and the like. In addition to simple excipients, lubricants such as magnesium stearate and talc may also be used. Examples of the liquid preparation for oral use include suspensions, solutions, emulsions, syrups and the like, and various excipients such as wetting agents, sweeteners, fragrances, preservatives, etc. in addition to commonly used diluents such as water and liquid paraffin . Formulations for parenteral administration include sterile aqueous solutions, non-aqueous solutions, suspensions, emulsions, freeze-dried preparations and suppositories. Examples of the suspending agent include propylene glycol, polyethylene glycol, vegetable oil such as olive oil, injectable ester such as ethyl oleate, and the like. Examples of the suppository base include witepsol, macrogol, tween 61, cacao paper, laurin, glycerogelatin and the like.

본 발명에 따른 약학적 조성물의 투여 경로는 이들로 한정되는 것은 아니지만 구강, 정맥내, 근육내, 동맥내, 골수내, 경막내, 심장내, 경피, 피하, 복강내, 비강내, 장관, 국소, 설하 또는 직장이 포함된다. 경구 또는 비경구 투하가 바람직하다. 본 발명에서 사용된 용어 "비경구"는 피하, 피내, 정맥내, 근육내, 관절내, 활액낭내, 흉골내, 경막내, 병소내 및 두개골내 주사 또는 주입기술을 포함한다. 본 발명의 약학적 조성물은 또한 직장 투여를 위한 좌제의 형태로 투여될 수 있다.The route of administration of the pharmaceutical composition according to the present invention may be, but is not limited to, oral, intravenous, intramuscular, intraarterial, intramedullary, intrathecal, intracardiac, transdermal, subcutaneous, intraperitoneal, intranasal, , Sublingual or rectal. Oral or parenteral administration is preferred. The term "parenteral" as used herein includes subcutaneous, intradermal, intravenous, intramuscular, intraarticular, intrasynovial, intrasternal, intrathecal, intralesional and intracranial injection or infusion techniques. The pharmaceutical compositions of the present invention may also be administered in the form of suppositories for rectal administration.

본 발명의 약학적 조성물은 사용된 특정 화합물의 활성, 연령, 체중, 일반적인 건강, 성별, 정식, 투여시간, 투여경로, 배출율, 약물 배합 및 예방 또는 치료될 특정 질환의 중증을 포함한 여러 요인에 따라 다양하게 변할 수 있고, 상기 약학적 조성물의 투여량은 환자의 상태, 체중, 질병의 정도, 약물 형태, 투여경로 및 기간에 따라 다르지만 당업자에 의해 적절하게 선택될 수 있고, 1일 0.0001 내지 50mg/kg 또는 0.001 내지 50mg/kg으로 투여할 수 있다. 투여는 하루에 한번 투여할 수도 있고, 수회 나누어 투여할 수도 있다. 상기 투여량은 어떠한 면으로든 본 발명의 범위를 한정하는 것은 아니다. 본 발명에 따른 약학적 조성물은 환제, 당의정, 캡슐, 액제, 겔, 시럽, 슬러리, 현탁제로 제형될 수 있다.The pharmaceutical composition of the present invention may be administered orally or parenterally depending on various factors including the activity of the specific compound used, age, weight, general health, sex, diet, time of administration, route of administration, rate of excretion, drug combination, And the dosage of the pharmaceutical composition may be appropriately selected by a person skilled in the art depending on the condition of the patient, the body weight, the degree of disease, the type of drug, the route of administration and the period of time, and is preferably from 0.0001 to 50 mg / kg or 0.001 to 50 mg / kg. The administration may be carried out once a day or divided into several times. The dose is not intended to limit the scope of the invention in any way. The pharmaceutical compositions according to the present invention can be formulated into pills, dragees, capsules, solutions, gels, syrups, slurries, suspensions.

본 발명의 또 다른 구현 예에 따르면, 본 발명은 박테리오파지 YMC11/02/R656 PAE BP [KCTC18363P]를 유효성분으로 포함하는 항생제를 제공한다.According to another embodiment of the present invention, the present invention provides an antibiotic comprising the bacteriophage YMC11 / 02 / R656 PAE BP [KCTC18363P] as an active ingredient.

대부분의 항생 물질들은 내성 증가에 직면함에 따라 갈수록 사용범위가 줄어들 수밖에 없는데 반해, 본 발명의 박테리오파지 YMC11/02/R656 PAE BP [KCTC18363P]를 유효성분으로 포함하는 항생제는 내성 문제를 근본적으로 해결할 수 있기에 그 만큼 항생제로서의 제품수명이 길어질 것으로 기대된다. 따라서, 병원성 세균인 녹농균을 특이적으로 사멸시키는 본 발명의 박테리오파지 YMC11/02/R656 PAE BP [KCTC18363P]를 유효성분으로 포함하는 항생제는 항균 효과, 살균 효과 및 방부 효과가 뛰어난 항생제로 유용하게 사용될 수 있다. 본 명세서에서 사용된 '항생제’라는 용어는 방부제, 살균제 및 항균제를 총칭한다.Antibiotics containing the bacteriophage YMC11 / 02 / R656 PAE BP [KCTC18363P] of the present invention as an active ingredient can fundamentally solve the resistance problem, while the antibiotics of most of the antibiotics are subject to an increase in resistance as the resistance increases. It is anticipated that the product life as antibiotics will be longer. Therefore, antibiotics containing the bacteriophage YMC11 / 02 / R656 PAE BP [KCTC18363P] of the present invention, which specifically kills the pathogenic bacterium Pseudomonas aeruginosa, as an active ingredient, can be effectively used as antibiotics excellent in antibacterial effect, have. The term " antibiotic " as used herein collectively refers to preservatives, bactericides and antibacterial agents.

또한, 본 발명의 또 다른 구현 예에 따르면, 본 발명은 상기 박테리오파지 YMC11/02/R656 PAE BP [KCTC18363P]를 유효성분으로 포함하는 소독제를 제공한다.According to another embodiment of the present invention, there is provided a disinfectant comprising the bacteriophage YMC11 / 02 / R656 PAE BP [KCTC18363P] as an active ingredient.

카바페넴 내성 녹농균에 대하여 특이적 사멸능을 갖는 본 발명의 박테리오파지 YMC11/02/R656 PAE BP [KCTC18363P]를 유효성분으로 포함하는 소독제는 병원 감염을 막기 위한 병원 및 보건용의 소독제로 유용하게 사용될 수 있고 또한, 일반 생활 소독제, 식품 및 조리 장소 및 설비의 소독제, 축산산업의 축사 소독제로서 유용하게 사용될 수 있다.The disinfectant containing the bacteriophage YMC11 / 02 / R656 PAE BP [KCTC18363P] of the present invention having the specific killing ability against carbapenem-resistant Pseudomonas aeruginosa is effective as a disinfectant for hospital and healthcare to prevent hospital infection Also, it can be usefully used as general disinfectant, disinfectant for food and cooking places and facilities, and as a barn disinfectant for the livestock industry.

본 발명의 또 다른 구현 예에 따르면, 항생제 내성 슈도모나스 균속에 의해 유발되는 질환의 개선용으로서 박테리오파지 YMC11/02/R656 PAE BP [KCTC18363P]를 유효성분으로 포함하는 식품 조성물을 제공한다.According to another embodiment of the present invention, there is provided a food composition containing bacteriophage YMC11 / 02 / R656 PAE BP [KCTC18363P] as an active ingredient for the improvement of diseases caused by antibiotic resistant Pseudomonas sp.

본 발명의 식품 조성물은 1 × 103 내지 1 × 1010 pfu/㎖의 박테리오파지를 포함하며, 바람직하게는 1 × 106 내지 1 × 109 pfu/㎖의 박테리오파지를 포함할 수 있다. The food composition of the present invention contains 1 × 10 3 to 1 × 10 10 pfu / ml of bacteriophage, preferably 1 × 10 6 to 1 × 10 9 pfu / ml of bacteriophage.

본 발명의 식품 조성물에 포함되는 박테리오파지 YMC11/02/R656 PAE BP [KCTC18363P]는 상술한 바와 같이, 항생제 내성 슈도모나스 균속, 바람직하게는 카바페넴 내성 녹농균을 특이적으로 사멸시키므로, 녹농균에 의해 유발되는 다양한 질환에 개선 효과를 나타낸다.As described above, the bacteriophage YMC11 / 02 / R656 PAE BP [KCTC18363P] contained in the food composition of the present invention specifically kills antibiotic-resistant Pseudomonas spp., Preferably carbapenem-resistant P. aeruginosa, And exhibits an improvement effect on the disease.

녹농균은 폐렴, 뇌수막염, 균혈증, 심내막염 및 내인성 기회감염 등을 일으키는 원인균으로서, 본 발명의 약학적 조성물은 녹농균에 의해 유발되는 다양한 질환(녹농균 유발성 질환), 예컨대 폐렴, 뇌수막염, 균혈증, 심내막염 및 내인성 기회감염 등에 대한 치료에 이용될 수 있다. Pseudomonas aeruginosa is a causative organism causing pneumonia, meningitis, bacteremia, endocarditis and endogenous opportunistic infections. The pharmaceutical composition of the present invention is useful as a medicament for treating various diseases caused by P. aeruginosa (Pseudomonas aeruginosa), such as pneumonia, meningitis, bacteremia, Opportunistic infections, and the like.

본 명세서에서 사용된 '개선'이라는 용어는 녹농균에 의해 유발된 질환의 경감을 의미한다.As used herein, the term " improvement " refers to alleviation of the disease caused by P. aeruginosa.

본 발명에서 식품 조성물은 각종 식품류, 예를 들어, 음료, 껌, 차, 비타민 복합제, 분말, 과립, 정제, 캡슐, 과자, 떡, 빵 등의 형태로 제조될 수 있다. 본 발명의 식품 조성물은 독성 및 부작용이 거의 없는 식물추출물로 구성된 것이므로 예방 목적으로 장기간 복용 시에도 안심하고 사용할 수 있다.The food composition of the present invention may be prepared in the form of various foods such as beverages, gums, tea, vitamin complexes, powders, granules, tablets, capsules, confectionery, rice cakes and breads. Since the food composition of the present invention is composed of a plant extract having little toxicity and side effects, it can be safely used for prolonged use even for prophylactic purposes.

여기서, 상기 식품 조성물이 음료 형태로 제조되는 경우 지시된 비율로 상기 식품 조성물을 함유하는 것 외에 특별한 제한점은 없으며 통상의 음료와 같이 여러가지 향미제 또는 천연 탄수화물 등을 추가 성분으로서 함유할 수 있다. 즉, 천연 탄수화물로서 포도당 등의 모노사카라이드, 과당 등의 디사카라이드, 슈크로스 등의 및 폴리사카라이드, 덱스트린, 시클로덱스트린 등과 같은 통상적인 당 및 자일리톨, 소르비톨, 에리트리톨 등의 당알콜 등을 포함할 수 있다. 상기 향미제로서는 천연 향미제(타우마틴, 스테비아 추출물(예를 들어 레바우디오시드 A, 글리시르히진등) 및 합성 향미제(사카린, 아스파르탐 등) 등을 들 수 있다. Here, when the food composition is prepared in a beverage form, there are no particular limitations other than those containing the food composition at the indicated ratios and may contain various flavors or natural carbohydrates such as ordinary beverages as an additional ingredient. That is, natural carbohydrates include monosaccharides such as glucose, disaccharides such as fructose, sucrose and the like and sugar sugars such as polysaccharide, dextrin and cyclodextrin, and sugar alcohols such as xylitol, sorbitol and erythritol can do. Examples of the above-mentioned flavors include natural flavors (such as tau martin and stevia extract (for example, rebaudioside A and glycyrrhizin) and synthetic flavors (for example, saccharine and aspartame).

그 외 본 발명의 식품 조성물은 여러 가지 영양제, 비타민, 광물(전해질), 합성 풍미제 및 천연 풍미제 등의 풍미제, 착색제, 펙트산 및 그의 염, 알긴산 및 그의 염, 유기산, 보호성 콜로이드 증점제, pH 조절제, 안정화제, 방부제, 글리세린, 알콜, 탄산 음료에 사용되는 탄산화제 등을 함유할 수 있다.In addition, the food composition of the present invention can be used as a flavoring agent such as various nutrients, vitamins, minerals (electrolytes), synthetic flavors and natural flavors, colorants, pectic acid and its salts, alginic acid and its salts, , a pH adjusting agent, a stabilizer, a preservative, a glycerin, an alcohol, a carbonating agent used in a carbonated drink, and the like.

이러한 성분은 독립적으로 또는 조합하여 사용할 수 있다. 이러한 첨가제의 비율은 그렇게 중요하진 않지만 본 발명의 식품 조성물 100 중량부 당 0.1 내지 약 50 중량부의 범위에서 선택되는 것이 일반적이다.These components may be used independently or in combination. The proportion of such additives is not so critical, but is generally selected in the range of 0.1 to about 50 parts by weight per 100 parts by weight of the food composition of the present invention.

본 발명에서 제공하는 신규한 박테리오파지는 강력한 항균제인 카바페넴 내성 슈도모나스 균속에 대하여 특이적 사멸능을 가지므로, 상기한 카바페넴 내성 슈도모나스 균속에 의해 유발되는 질환의 예방 및 치료 목적으로 활용할 수 있다.The novel bacteriophage provided in the present invention has a specific killing activity against carbapenem-resistant Pseudomonas sp., A potent antimicrobial agent, and thus can be utilized for the prevention and treatment of diseases caused by carbapenem-resistant Pseudomonas sp.

도 1은 실시예 1에서 카바페넴에 대해 내성을 갖는 녹농균 29주를 나타낸 것이다.
도 2는 실시예 2에서 카바페넴에 대해 내성을 갖는 녹농균에 용균성 박테리오파지를 접종한 후 플라크가 형성된 모습을 사진으로 나타낸 것이다.
도 3은 실시예 3에서 카베페넴에 대해 내성을 갖는 녹농균에 대한 용균성 박테리오파지 YMC11/02/R656 PAE BP의 TEM 이미지를 나타낸 것이다.
도 4는 실시예 4에서 카베페넴에 대해 내성을 갖는 녹농균에 대한 용균성 박테리오파지 YMC11/02/R656 PAE BP의 각 온도 별로 안정성을 평가하여 그래프로 나타낸 것이다.
도 5는 실시예 4에서 카베페넴에 대해 내성을 갖는 녹농균에 대한 용균성 박테리오파지 YMC11/02/R656 PAE BP의 각 pH 별로 안정성을 평가하여 그래프로 나타낸 것이다.
도 6은 실시예 5에서 카바페넴에 대해 내성을 갖는 녹농균에 대한 용균성 박테리오파지 YMC11/02/R656 PAE BP의 흡착능을 그래프로 나타낸 것이다.
도 7은 실시예 5에서 카바페넴에 대해 내성을 갖는 녹농균에 대한 용균성 박테리오파지 YMC11/02/R656 PAE BP의 1단 증식 곡선을 나타낸 것이다.
도 8은 실시예 6에서 카바페넴에 대해 내성을 갖는 녹농균에 대한 용균성 박테리오파지 YMC11/02/R656 PAE BP의 전체 유전체 서열분석(whole genome sequence analysis)을 나타낸 것이다.
도 9는 실시예 6에서 카바페넴에 대해 내성을 갖는 녹농균에 대한 용균성 박테리오파지 YMC11/02/R656 PAE BP의 전체 유전체 서열분석 중 ORF(Open reading frame) 분석 결과를 나타낸 것이다.
도 10은 실시예 6에서 카바페넴에 대해 내성을 갖는 녹농균에 대한 용균성 박테리오파지 YMC11/02/R656 PAE BP의 기능이 알려진 11개의 ORF 중 슈도모나스 박테리오파지 PA1/KOR/2010와 전혀 상이한 서열을 갖는 8개의 ORF를 나타낸 것이다.
도 11은 실시예 6에서 카바페넴에 대해 내성을 갖는 녹농균에 대한 용균성 박테리오파지 YMC11/02/R656 PAE BP와 슈도모나스 박테리오파지 PAJU2(YP_002284361.1)의 용균성에 관련된 후보 단백질(엔돌리신/홀린)의 아미노산 서열 차이를 나타낸 것이다.
도 12는 실시예 7에서 생체 외(in vitro)에서 박테리오파지 YMC11/02/R656 PAE BP의 카바페넴에 대해 내성을 갖는 녹농균에 대한 용균능을 분석하여 나타낸 것이다.
도 13은 실시예 8에서 마우스의 비강을 통해 카바페넴에 대해 내성을 갖는 녹농균을 감염시킨 뒤 박테리오파지 YMC11/02/R656 PAE BP의 처리에 따른 마우스의 생존율 변화를 그래프로 나타낸 것이다.
도 14는 실시예 9에서 마우스의 폐에 카바페넴에 대해 내성을 갖는 녹농균을 감염시킨 뒤 박테리오파지 YMC11/02/R656 PAE BP의 처리에 따른 폐 조직의 모습을 사진으로 나타낸 것이다.
도 15는 실시예 9에서 마우스의 폐에 카바페넴에 대해 내성을 갖는 녹농균을 감염시킨 뒤 박테리오파지 YMC11/02/R656 PAE BP의 처리에 따른 병증 심각도(histological score)의 변화를 그래프로 나타낸 것이다.
도 16은 실시예 9에서 마우스의 폐에 카바페넴에 대해 내성을 갖는 녹농균을 감염시킨 뒤 박테리오파지 YMC11/02/R656 PAE BP의 처리에 따른 녹농균의 수의 변화를 그래프로 나타낸 것이다.Fig. 1 shows 29 pseudomonas aeruginosa strains resistant to carbapenem in Example 1. Fig.
Fig. 2 is a photograph showing a state in which a plaque is formed after inoculation of a bacterial bacteriophage into P. aeruginosa resistant to carbapenem in Example 2. Fig.
FIG. 3 shows a TEM image of a bacteriophage YMC11 / 02 / R656 PAE BP against P. aeruginosa resistant to carbepenem in Example 3. FIG.
Fig. 4 is a graph showing the stability of each of the temperatures of the bacteriophage YMC11 / 02 / R656 PAE BP against pseudomonas aeruginosa resistant to carbepenem in Example 4. Fig.
FIG. 5 is a graph showing the stability of each of the pHs of the soluble bacteriophage YMC11 / 02 / R656 PAE BP against P. aeruginosa resistant to carbepenem in Example 4. FIG.
6 graphically illustrates the adsorptivity of the bacteriophage YMC11 / 02 / R656 PAE BP against P. aeruginosa resistant to carbapenem in Example 5. FIG.
Fig. 7 shows a single-step growth curve of the bacteriophage YMC11 / 02 / R656 PAE BP against P. aeruginosa resistant to carbapenem in Example 5. Fig.
Figure 8 shows a whole genome sequence analysis of the bacteriophage YMC11 / 02 / R656 PAE BP against P. aeruginosa resistant to carbapenem in Example 6.
9 shows the ORF (open reading frame) analysis result of the entire genome sequence analysis of the bacteriophage YMC11 / 02 / R656 PAE BP against P. aeruginosa resistant to carbapenem in Example 6. Fig.
10 is a graph showing the results of analysis of the activity of eight bacterial bacteriophage YMC11 / 02 / R656 PAE BPs against Pseudomonas aeruginosa having resistance to carbapenem in Example 6 in eight ORFs having a completely different sequence from Pseudomonas bacteriophage PA1 / KOR / 2010 ORF.
11 is a graph showing the activity of the candidate protein (endolysin / holin) related to the fungi of the bacteriophage YMC11 / 02 / R656 PAE BP and Pseudomonas bacteriophage PAJU2 (YP_002284361.1) against P. aeruginosa resistant to carbapenem in Example 6, ≪ / RTI >
FIG. 12 shows the potency of P. aeruginosa resistant to carbapenem of bacteriophage YMC11 / 02 / R656 PAE BP in vitro in Example 7.
FIG. 13 is a graph showing changes in survival rate of mice according to treatment with bacteriophage YMC11 / 02 / R656 PAE BP after infecting with P. aeruginosa resistant to carbapenem through mouse nasal passages in Example 8. FIG.
Fig. 14 is a photograph showing the appearance of lung tissue according to the treatment of bacteriophage YMC11 / 02 / R656 PAE BP after infecting P. aeruginosa resistant to carbapenem in the mouse lung in Example 9; Fig.
FIG. 15 is a graph showing changes in the histological score according to the treatment of bacteriophage YMC11 / 02 / R656 PAE BP after infection with P. aeruginosa resistant to carbapenem in the mouse lung in Example 9. FIG.
16 is a graph showing changes in the number of P. aeruginosa after treatment with bacteriophage YMC11 / 02 / R656 PAE BP after infecting P. aeruginosa resistant to carbapenem in the mouse lung in Example 9.

이하, 본 발명을 하기의 실시예에 의해 상세히 설명한다. 단, 하기 실시예는 본 발명을 예시하는 것일 뿐, 본 발명의 내용이 하기 실시예에 의해 한정되는 것은 아니다. Hereinafter, the present invention will be described in detail with reference to the following examples. However, the following examples are illustrative of the present invention, and the contents of the present invention are not limited by the following examples.

실시예Example 1:  One: 카바페넴Carbapenem 내성 임상 검체 분리 균주 수집 및 균주 은행 구축 Collection of isolates of resistant clinical specimens and establishment of strain bank

(1) 임상 검체 분리 균주 수집: 인덱스 균주 은행 구축(1) Collection of isolates of clinical specimens: Establishment of index strain bank

세브란스 병원의 환자들로부터 호흡기 감염증, 패혈증 및 농양 검체를 수집하였으며 각 검체에 대한 임상적 위중도 평가 기준은 다음과 같다. 호흡기 검체는 그룹 4,5,6으로 제한하였고, 패혈증 검체는 3쌍 배양 중 2쌍 이상에서 증식하였으며, 농양 검체는 심부농양 주사기 아스피레이트에 제한하였다. 상기 검체로부터 슈도모나스 균속에 속하는 병원균을 배양 분리하였고, 균주의 동정을 위해 전통적 방법을 통한 생화학적 동정 혹은 16s rRNA/ITS/rpoB 염기서열 분석을 통한 분자역학적 방법을 실시하였다. 감수성 결과는 Clinical and Laboratory Standards Institute (CLSI, 2009)를 기준으로 판독하였다. 감수성 시험은 뮬러-힌튼(Mueller-Hinton) 아가를 사용하여 외기 37℃에서 하룻밤 동안 배양하는 CLSI 디스크 확산 시험방법을 사용하였다. 슈도모나스 균속에 대한 시험 항균제는 아미카신(Amikacin), 아즈트레오남(Aztreonam), 세즈타지딤(Ceftazidime), 시프로플록사신(Ciprofloxacin), 콜리스틴(Colistin), 세페핌(Cefepime), 젠타마이신(Gentamicin), 이미페넴(Imipenem), 레보플록사신(Levofloxacin), 메로페넴(Meropenem), 피페라실린(Piperacillin), 피페라실린/타조박탐(Piperacillin/Tazobactam), 티카실린(Ticarcillin), 토브라마이신(Tobramycin)을 사용하였다. 카바페넴 내성 균주을 선별하기 위해 이미페넴 호지 테스트(Imipenem Hodge test)를 통해 카바페넴아제를 발현하는 균주를 선별하였다. 이 때, 메탈로-β-락타마제(metallo-β-lactamase)와 세린-β-락타마제(serin-β-lactamase)를 포함한 카바페넴아제(carbapenemases)의 PCR 스크리닝 프라이머 세트는 하기 표 1에 나타내었다.Respiratory infections, sepsis, and abscesses were collected from patients at Severance Hospital. Clinical severity ratings for each sample were as follows. Respiratory specimens were restricted to groups 4,5,6, and sepsis samples proliferated in more than two pairs of triplicate cultures. Abscess specimens were restricted to deep abscess syringe aspirate. Pseudomonas species belonging to the genus Pseudomonas were isolated from the specimens. Molecular epidemiological methods were performed by biochemical identification or 16s rRNA / ITS / rpoB sequencing. Sensitivity results were read based on the Clinical and Laboratory Standards Institute (CLSI, 2009). The susceptibility test was performed using a CLSI disk diffusion test method in which Mueller-Hinton agar was used to culture at ambient temperature at 37 ° C overnight. Test antimicrobial agents against Pseudomonas spp. Include Amikacin, Aztreonam, Ceftazidime, Ciprofloxacin, Colistin, Cefepime, Gentamicin, , Imipenem, Levofloxacin, Meropenem, Piperacillin, Piperacillin / Tazobactam, Ticarcillin and Tobramycin were used. Respectively. In order to screen for carbapenem-resistant strains, strains expressing carbapenemase were selected through the Imipenem Hodge test. At this time, a PCR screening primer set of carbapenemases including metallo-beta-lactamase and serine-beta-lactamase is shown in Table 1 below .

타겟(target)Target 프라이머(primer)Primer 프라이머 서열(5'-3')The primer sequence (5'-3 ') 결과물 크기Product Size blaVIMblaVIM VIM2FR-FVIM2FR-F ATGTTCAAACTTTTGAGTAAGATGTTCAAACTTTTGAGTAAG 801bp801bp VIM2FR-RVIM2FR-R CTACTCAACGACTGAGCGCTACTCAACGACTGAGCG blaIMP bla IMP IMP1-FIMP1-F CATGGTTTGGTGGTTCTTGTCATGGTTTGGTGGTTCTTGT 450bp450bp IMP1-RIMP1-R ATAATTTGGCGGACTTTGGCATAATTTGGCGGACTTTGGC blaSIM-1 bla SIM-1 SIM-1 MP FSIM-1 MP F TACAAGGGATTCGGCATCGTACAAGGGATTCGGCATCG 571bp571bp SIM-1 MR RSIM-1 MR R TAATGGCCTGTTCCCATGTGTAATGGCCTGTTCCCATGTG blaSPM-1 bla SPM-1 SPM-1-ASPM-1-A CTGCTTGGATTCATGGGCGCCTGCTTGGATTCATGGGCGC 784bp784bp SPM-1-BSPM-1-B CCTTTTCCGCGACCTTGATCCCTTTTCCGCGACCTTGATC blaGIM-1 bla GIM-1 GIM1-FGIM1-F ATTACTTGTAGCGTTGCCAGCTATTACTTGTAGCGTTGCCAGCT 726bp726bp GIM1-RGIM1-R TAATCAGCCGACGCTTCAGTAATCAGCCGACGCTTCAG blaAIM-1 bla AIM-1 Yong MBLFYong MBLF GGCATTGATGCGCATCAAGGGGCATTGATGCGCATCAAGG 726bp726bp Yong MBLRFYong MBLRF GAAGACGTCGTCCGAGATCGGAAGACGTCGTCCGAGATCG blaNDM-1 bla NDM-1 KP05506 M13 R3KP05506 M13 R3 CAATATTATGCACCCGGTCGCAATATTATGCACCCGGTCG 726bp726bp KP05506 M13 R2KP05506 M13 R2 ATCATGCTGGCCTTGGGGAAATCATGCTGGCCTTGGGGAA blaHKM-1 bla HKM-1 KHM-1 FKHM-1 F GGTATGCGCTGACGATTCATGGTATGCGCTGACGATTCAT 526bp526bp KHM-1 RKHM-1 R TACCGCATGGCTAAGATTGCTACCGCATGGCTAAGATTGC blaSME bla SME SME1-3 FSME1-3 F AGCGGTTCCCTTTATGCAGTAGCGGTTCCCTTTATGCAGT 661bp661bp SME1-3 RSME1-3 R CGTGATGCTTCCGCAATAGTCGTGATGCTTCCGCAATAGT blaIMI, blaNMC bla IMI, bla NMC IMI NMC FIMI NMC F CGATTGGGTAGTTGGCGATACGATTGGGTAGTTGGCGATA 173bp173bp IMI NMC RIMI NMC R CGATTCTTGAAGCTTCTGCGCGATTCTTGAAGCTTCTGCG blaGES bla GES GES 2456 FGES 2456 F CGAAAAAGCAGCTCAGATCGCGAAAAAGCAGCTCAGATCG 761bp761 bp GES 2456 RGES 2456 R TGTCCGTGCTCAGGATGAGTTGTCCGTGCTCAGGATGAGT blaKPC bla KPC KPC 1-4 FKPC 1-4 F TGGACACACCCATCCGTTACTGGACACACCCATCCGTTAC 515bp515bp KPC 1-4 RKPC 1-4 R GACGGCCAACACAATAGGTGGACGGCCAACACAATAGGTG

(단, 세포불멸화(immortalization)은 -70℃ 초저온 냉동고에서 10% 글리세롤 스톡(glycerol stock)으로 수행하였다.)(However, cell immortalization was performed with 10% glycerol stock in a -70 ° C cryocooler.)

수집된 녹농균(Pseudomonas aeruginosa ) 중 29주가 카바페넴에 대한 내성을 나타내었다(도 1). The collected Pseudomonas aeruginosa ) showed resistance to carbapenem (Fig. 1).

단, 도 1에서 S, I 및 R은 항균제에 대한 감수성을 평가한 결과로, 'S'는 민감(Susceptible), 'I'는 중간(Intermediate), 'R'은 내성(Resistant)를 의미한다.In FIG. 1, S, I and R are the results of evaluating the susceptibility to the antimicrobial agent, wherein 'S' means susceptible, 'I' means intermediate, and 'R' means resistant .

실시예Example 2. 파지 은행 구축을 위한 검체 수집 및 파지 분리 정제 2. Sample collection and phage separation purification for phage bank establishment

(1) 파지 은행 구축을 위한 검체 수집(1) Collection of samples for phage bank establishment

세브란스 병원의 오수 처리시설에서 최초 침전지를 거친 후 부유물질 및 침사물이 제거된 처리수 2L를 채취하였다. 이는 화학처리 시설 전 단계의 오수로 제한하였다. 수집한 시료에 1L당 염화나트륨 58g을 첨사한 후 10,000g에서 10분간 원심 분리하여 200nm 밀리포어 필터로 여과하였다. 얻어진 여과액에 폴리에틸렌글리콜(PEG, 분자량 8,000)을 10% V/V으로 첨가하고 4℃에서 12시간 동안 냉장 보관하였다. 12시간 냉장 보관된 여과액을 12,000g에서 20분간 원심 분리하여 침전물을 파지 희석 완충액 (SM 완충액)에 재부유하여 냉동 보관하였다. 이를 3회 반복하여 300mL의 박테리오파지 부유액을 채취하였다. In the sewage treatment facility of Severance Hospital, 2L of treated water from which the suspended matter and sediment were removed after the first sedimentation basin was collected. This was limited to sewage at the pre-stage of the chemical treatment facility. 58 g of sodium chloride per 1 L was added to the collected samples, followed by centrifugation at 10,000 g for 10 minutes and filtration through a 200 nm Millipore filter. Polyethylene glycol (PEG, molecular weight 8,000) was added to the obtained filtrate at 10% V / V and stored at 4 占 폚 for 12 hours in a refrigerator. The 12-hour-refrigerated filtrate was centrifuged at 12,000 g for 20 minutes and the precipitate was resuspended in a digestion buffer (SM buffer) and stored frozen. This was repeated three times to collect 300 mL of the bacteriophage suspension.

(2) 용균성 파지 선별 및 정제(2) Screening and purification of bacteria-resistant phage

① 스팟 테스트(Spot test) 및 플라그 분석(Plaque assay)을 이용한 파지 정제 ① Phage purification using spot test and plaque assay

용균성 파지의 분리 정제는 스팟 테스트(Spot Test)법 (Mazzocco A et al. In Bacteriophages, Clokie and Kropinski AM, eds. Humana Press. 2009)으로 실행하였다. 확보된 균주를 맥콘키 한천배지에서 접종 후 외기 35℃에서 하룻밤 동안 배양하였다. 배양 후, 투명한 플라크 형성을 보고 파지에 감수성인 균주를 선별하였다(도 2). 감수성인 균주를 맥콘키 한천배지에 접종하여 35℃에서 12시간 동안 배양하였다. 살린 1ml 튜브에 McFarland 0.5 탁도로 각 균주의 현탁액 제조하고 H 탑 아가 (3 ml), 감수성 박테리아 100ul 및 파지 용액 (각각 1ul, 10ul 및 50ul)을 섞어 LB 아가에 도포한 후, 35℃에서 12시간 동안 배양하였다. 플라크 관찰한 후에 파스퇴르 파이펫으로 플라크를 채취하여 SM 완충용액에 희석하고 다시 감수성인 균주 현탁액을 이용하여 3회 반복 정제하였다. 이렇게 얻어진 순수한 박테리오파지는 SM 완충용액에 희석하고 다시 감수성인 균주 현탁액을 이용하여 3회 반복 정제하였다. 이렇게 얻어진 순수한 박테리오파지는 SM 완충용액에 희석하여 보관하였다.The separation and purification of the soluble phage was carried out by the spot test method (Mazzocco A et al. In Bacteriophages, Clokie and Kropinski AM, eds Humana Press. The obtained strains were inoculated on a McConki agar medium and incubated overnight at ambient temperature of 35 ° C. After cultivation, transparent plaque formation was observed, and strains susceptible to phage were selected (Fig. 2). The susceptible strains were inoculated on a McConki agar medium and cultured at 35 DEG C for 12 hours. (1 ml, 10 ul and 50 ul, respectively) were added to the LB agar, and the mixture was incubated at 35 ° C for 12 hours Lt; / RTI > After plaque observation, plaques were taken with Pasteur pipette, diluted in SM buffer, and repeatedly refined three times using a susceptible strain suspension. The pure bacteriophage thus obtained was diluted in SM buffer solution and subjected to repeated purification three times using a susceptible strain suspension. The pure bacteriophage thus obtained was diluted with SM buffer solution and stored.

② 용균성 파지의 용균역가 측정② Measuring the lytic activity of the bacterium phage

실시예 1에서 확인한 카바페넴 내성 녹농균 29주 각각을 맥콘키 한천배지에서 접종하여 배양한 후, 정제된 박테리오파지 YMC11/02/R656 PAE BP를 도말된 각각의 균주에 5ul로 접종하여 플라그 형성을 확인하고, 역가 범위를 확인하였다. 그 결과, 카바페넴 내성 녹농균 29주 중 11주(38%)를 용균시킨 것을 확인할 수 있었다(표 2).Resistant 29 isolates of carbapenem-resistant P. aeruginosa identified in Example 1 were inoculated and cultured on a McConki agar medium, and the purified bacteriophage YMC11 / 02 / R656 PAE BP was inoculated at 5 ul into each of the cultivated strains to confirm plaque formation , And the potency range was confirmed. As a result, it was confirmed that 11 out of 29 (38%) of carbapenem-resistant P. aeruginosa were lysed (Table 2).

카바페넴 내성 녹농균주Carbapenem resistant pseudomonas aeruginosa 박테리오파지 YMC11/02/R656 PAE BP의 용균성Solubility of bacteriophage YMC11 / 02 / R656 PAE BP YMC11/02/R656YMC11 / 02 / R656 ++++ YMC12/01/R1679YMC12 / 01 / R1679 ++++ YMC12/01/R1561YMC12 / 01 / R1561 -- YMC12/01/R2799-2YMC12 / 01 / R2799-2 ++ YMC12/01/R2928-2YMC12 / 01 / R2928-2 -- YMC12/02/R3223-2YMC12 / 02 / R3223-2 ++ YMC12/02/R3040YMC12 / 02 / R3040 ++ YMC12/03/R439-2YMC12 / 03 / R439-2 -- YMC11/01/R263YMC11 / 01 / R263 ++++ YMC12/01/R21YMC12 / 01 / R21 -- YMC11/03/P287YMC11 / 03 / P287 -- YMC11/03/U2281YMC11 / 03 / U2281 -- YMC11/11/R1836YMC11 / 11 / R1836 ++ YMC11/06/C171YMC11 / 06 / C171 -- YMC12/01/R24YMC12 / 01 / R24 ++ YMC12/01/R437YMC12 / 01 / R437 ++ YMC12/01/R1323YMC12 / 01 / R1323 -- YMC11/05/P144YMC11 / 05 / P144 ++ YMC11/07/P54YMC11 / 07 / P54 -- YMC11/07/R521-2YMC11 / 07 / R521-2 -- YMC12/01/R960YMC12 / 01 / R960 -- YMC12/01/R2316YMC12 / 01 / R2316 ++ YMC12/01/R2767YMC12 / 01 / R2767 -- YMC12/03/R469YMC12 / 03 / R469 -- YMC12/03/R745YMC12 / 03 / R745 -- YMC11/01/R31YMC11 / 01 / R31 -- YMC11/02/R234YMC11 / 02 / R234 -- YMC11/06/U973-2YMC11 / 06 / U973-2 -- YMC11/08/R25YMC11 / 08 / R25 --

단, 상기 표 2에서 ++, + 및 -는 수집된 균주에 대한 플라크 활성을 평가한 것으로, '++'는 투명한 플라크(clear plaque), '+'는 혼탁 플라크(turbid plaque)를 의미한다.In Table 2, ++, + and - indicate the evaluation of plaque activity for the collected strains, "++" means a clear plaque and "+" means a turbid plaque .

실시예Example 3.  3. 카바페넴Carbapenem 내성 녹농균에 대한  Resistant to Pseudomonas aeruginosa 용균성Solvent strength 박테리오파지의 전자 현미경 분석 Electron microscopic analysis of bacteriophages

정제된 박테리오파지를 감수성 균주 배양 배지(20ml LB 배지)에 접종 및 배양한 뒤 220nm 밀리포어 필터로 여과하고 상청액에 폴리에틸렌글리콜(MW 8,000)을 10%(w/v)의 양으로 첨가한 후 밤새 냉장 보관하였다. 이후 12,000g의 조건으로 20분 동안 원심 분리한 뒤, 에너지 여과 투과 전자현미경(Energy-Filtering Transmission Electron Microscope)을 이용하여 박테리오파지의 형태를 분석했다. The purified bacteriophage was inoculated and cultured in a susceptible strain culture medium (20 ml of LB medium) and then filtered with a 220 nm Millipore filter. To the supernatant was added polyethylene glycol (MW 8,000) in an amount of 10% (w / v) Respectively. After centrifugation at 12,000 g for 20 minutes, the shape of the bacteriophage was analyzed using an Energy-Filtering Transmission Electron Microscope.

형태적으로 짧은 꼬리와 육각형 머리를 가지는 단축 100 nm, 장축 200 nm 정도의 파지며, 분류상 포도비리대(Podoviridae)에 속하는 것으로 분류했다(도 3).It is classified as belonging to Podoviridae (Fig. 3), with a short axis of 100 nm and a long axis of about 200 nm, with short tail and hexagonal heads in morphology.

실시예Example 4. 정제된 박테리오파지  4. Purified bacteriophage YMC11YMC11 /02/R656 / 02 / R656 PAEPAE BP의 온도 및 pH 안정성 분석 Analysis of temperature and pH stability of BP

SM 버퍼 40ul에 정제된 박테리오파지 YMC11/02/R656 PAE BP 1ul를 넣고, 4℃, 40℃, 50℃, 60℃, 70℃에서 10분 간격으로 1시간 동안 배양한 후 숙주 세포와 함께 플라그 분석을 수행하였다. 40 μl of SM buffer was added with 1 μl of purified bacteriophage YMC11 / 02 / R656 PAE BP and incubated at 4 ° C, 40 ° C, 50 ° C, 60 ° C, and 70 ° C for 10 min at intervals of 10 min. Respectively.

또한, pH가 4, 5, 7, 7.5, 8, 9, 10인 SM 버퍼 각각에 정제된 박테리오파지 YMC11/02/R656 PAE BP 1ul를 넣고 4℃에서 5일 동안 배양한 후 숙주 세포와 함께 플라그 분석을 수행하였다.In addition, 1 μl of purified bacteriophage YMC11 / 02 / R656 PAE BP was added to SM buffers with pH values of 4, 5, 7, 7.5, 8, 9 and 10, and incubated at 4 ° C for 5 days. Respectively.

그 결과, 박테리오파지 YMC11/02/R656 PAE BP는 4℃에서 안정성이 높고, 40℃에서도 1시간 까지는 대략 87%의 높은 활성을 유지하는 것을 확인할 수 있었다(도 4).As a result, it was confirmed that the bacteriophage YMC11 / 02 / R656 PAE BP had high stability at 4 DEG C and maintained a high activity of about 87% at 40 DEG C for up to 1 hour (FIG. 4).

또한, 박테리오파지 YMC11/02/R656 PAE BP는 24시간까지 넓은 pH 범위에서 안정성을 나타냈고, 5일까지 pH 7에서는 비교적 높은 안정성을 유지하는 것을 볼 수 있었다(도 5).In addition, the bacteriophage YMC11 / 02 / R656 PAE BP showed stability over a wide pH range up to 24 hours and maintained a relatively high stability at pH 7 until 5 days (FIG. 5).

실시예Example 5. 녹농균에 대한 박테리오파지  5. Bacteriophage against Pseudomonas aeruginosa YMC11YMC11 /02/R656 / 02 / R656 PAEPAE BP의  BP 흡착능Adsorption capacity 및 1단 증식 곡선(one-step growth curve) 분석 And one-step growth curve analysis

카바페넴 내성 녹농균을 OD 값이 0.5가 되도록 배양한 뒤, 녹농균에 정제된 박테리오파지 YMC11/02/R656 PAE BP를 MOI 0.001로 넣고 상온에서 배양하였다. 100ul 시료를 1, 2, 3, 4, 5, 10, 15, 20분에 1ml씩 채취하여 LB 배지에 희석한 뒤 플라그 분석을 통해 상기 박테리오파지의 흡착능을 평가하였다.The carbapenem-resistant P. aeruginosa was cultivated at an OD value of 0.5, and the bacteriophage YMC11 / 02 / R656 PAE BP purified with P. aeruginosa was added at a MOI of 0.001 and cultured at room temperature. 1 ml of each 100 μl sample was collected at 1, 2, 3, 4, 5, 10, 15, and 20 minutes, diluted in LB medium, and then adsorbed to the bacteriophage by plaque analysis.

또한, 카바페넴 내성 녹농균을 OD 값이 0.3이 되도록 배양한 뒤, 4℃에서 5분 동안 7,000g로 원심 분리하여 세포를 침강시킨 후, 0.5ml의 LB 배지에 희석시키고, 정제된 박테리오파지 YMC11/02/R656 PAE BP를 MOI 0.001(titer 108pfu/cells)로 넣고 37℃에서 5분 동안 배양하였다. 배양된 혼합 시료를 13,000g에서 1분동안 원심 분리하여 얻어진 펠렛을 10ml의 LB 배지에 희석시키고 37℃에서 배양하였다. 배양 도중 5분 마다 시료를 채취하여 플라그 분석을 통해 상기 박테리오파지의 1단 증식 곡선을 평가하였다.In addition, carbapenem-resistant P. aeruginosa was cultured to an OD value of 0.3, followed by centrifugation at 7,000 g for 5 minutes at 4 ° C to precipitate the cells. Then, the cells were diluted in 0.5 ml of LB medium and purified bacteriophage YMC11 / 02 / R656 PAE BP was added at a MOI of 0.001 (titer 10 8 pfu / cells) and incubated at 37 ° C for 5 minutes. The cultured mixed sample was centrifuged at 13,000 g for 1 minute, and the resulting pellet was diluted in 10 ml of LB medium and cultured at 37 ° C. Samples were collected every 5 minutes during the culturing, and the 1-fold growth curve of the bacteriophage was evaluated through plaque analysis.

그 결과, 박테리오파지 YMC11/02/R656 PAE BP의 접종 후 10분 이내에 박테리오파지의 99% 이상이 녹농균에 대하여 흡착하는 것을 확인할 수 있었고(도 6), 499 PFU/감염 세포의 높은 버스트 사이즈(burst size)를 나타내었다(도 7).As a result, it was confirmed that more than 99% of the bacteriophages were adsorbed to P. aeruginosa within 10 minutes after the inoculation of the bacteriophage YMC11 / 02 / R656 PAE BP (Fig. 6), and the high burst size of 499 PFU / (Fig. 7).

실시예 6. 분리된Example 6. Separated 박테리오파지  Bacteriophage YMC11YMC11 /02/R656 / 02 / R656 PAEPAE BP의 전체 게놈 서열 분석 Whole genome sequencing of BP

전 유전체 서열분석을 통해 YMC11/02/R656 PAE BP의 전 유전체 (60,919bp. 113 ORF, G+C 함량 58.7%)를 분석하였다 (도 8). 113개의 ORF 중 11개의 OFR만이 기능 단백질이었다(도 9). 이들 11개 ORF(ORF17, 18, 23, 41, 45, 64, 76, 98, 99, 103, 108)의 핵산 서열은 서열번호 2 내지 12으로 표시된다.The entire genome of the YMC11 / 02 / R656 PAE BP (60,919 bp. 113 ORF, G + C content of 58.7%) was analyzed by the whole genome sequence analysis (FIG. Of the 113 ORFs, only 11 OFRs were functional proteins (Fig. 9). Nucleic acid sequences of these 11 ORFs (ORF 17, 18, 23, 41, 45, 64, 76, 98, 99, 103 and 108) are represented by SEQ ID NOS: 2 to 12.

또한, 본 박테리오파지는 종래의 슈도모나스 박테리오파지 PAJU2와 기능이 알려진 11개의 ORF 중 7개의 ORF(ORF17, 18, 23, 45, 76, 98, 99)가 전혀 상이하고(도 10), 용균성에 관련된 후보 단백질 중 엔돌리신(Endolysin; Genbank no. YP_002284361.1)과는 4개의 아미노산 서열에 차이가 있었으며(도 11(a)), 홀린(Holin)은 본 박테리오파지 서열에서 발견되지 않는 것을 확인할 수 있었다(도 11(b)).This bacteriophage differs from the conventional Pseudomonas bacteriophage PAJU2 in that the seven ORFs (ORF 17, 18, 23, 45, 76, 98, 99) out of the 11 ORFs functioning in the present invention are completely different (FIG. 10) There was a difference in the four amino acid sequences of endolysin (Genbank no. YP_002284361.1) among proteins (Fig. 11 (a)), confirming that Holin was not found in this bacteriophage sequence 11 (b)).

실시예Example 7. 생체 외  7. In vitro 카바페넴Carbapenem 내성 녹농균에 대한 박테리오파지의  Of bacteriophage against resistant P. aeruginosa 용균능Drag force 검증 Verification

카바페넴 내성 녹농균 1 X 109 CFU/ml에 준비된 박테리오파지 YMC11/02/R656 PAE BP를 1 X 108 CFU/ml(MOI: 0.1), 1 X 109 PFU/ml(MOI: 1), 1 X 1010 PFU/ml(MOI: 10)의 양으로 각각 처리하고 시간 별로 OD 값(파장 600nm)을 측정하였다. 단, 대조군으로는 PBS+SM 버퍼를 처리하였다. Cover penem-resistant Pseudomonas aeruginosa 1 X 10 9 bacteriophage prepared in CFU / ml YMC11 / 02 / R656 PAE BP to 1 X 10 8 CFU / ml ( MOI: 0.1), 1 X 10 9 PFU / ml (MOI: 1), 1 X 10 10 PFU / ml (MOI: 10), and the OD value (wavelength: 600 nm) was measured with respect to time. However, the control group was treated with PBS + SM buffer.

대조군과 비교할 때, 녹농균에 대하여 박테리오파지 YMC11/02/R656 PAE BP를 처리한 경우 OD값이 감소하는 것을 볼 수 있었고, 특히 MOI 값이 증가할수록 OD값이 더욱 감소하는 것을 볼 수 있었다. Compared with the control group, OD value decreased when bacteriophage YMC11 / 02 / R656 PAE BP was treated against P. aeruginosa. In particular, OD value decreased with increasing MOI value.

이를 통하여, 본 발명에 따른 박테리오파지 YMC11/02/R656 PAE BP는 카바페넴 내성 녹농균에 대하여 용균성을 갖는 것을 알 수 있다(도 12).Thus, it can be seen that the bacteriophage YMC11 / 02 / R656 PAE BP according to the present invention has a tolerance to carbapenem-resistant Pseudomonas aeruginosa (FIG. 12).

실시예Example 8. 마우스의 비강 내 녹농균 감염에 대한 박테리오파지의  8. Bacteriophage to nasal pseudomonas infestation of mouse 용균능Drag force 검증 Verification

생후 7주된 암컷 B6 마우스 30마리를 1세트로 준비하고, 각 마우스에 시클로포스파미드(cyclophosphamide)를 4mg씩 2회 처리한 뒤, 졸레틸(30mg/kg)과 롬푼(10mg/kg)으로 마취시켰다. 이후, 각 마우스의 비강 내로 카바페넴 내성 녹농균 1 X 109 CFU/ml (620nm=0.6)를 접종하고 30분 후 하기 표 3과 같이 준비된 박테리오파지 YMC11/02/R656 PAE BP를 접종한 뒤 12일간 사육하면서 체중 변화와 생존 여부를 관찰하였다.Each of the mice was treated with cyclophosphamide (4 mg each) twice, and the mice were anesthetized with zoletyl (30 mg / kg) and lompun (10 mg / kg) . Subsequently, 1 × 10 9 CFU / ml (620 nm = 0.6) of carbapenem-resistant Pseudomonas aeruginosa resistant to carbapenem was inoculated into the nasal cavities of each mouse. After 30 minutes, the bacteriophage YMC11 / 02 / R656 PAE BP prepared as shown in Table 3 was inoculated, And weight change and survival were observed.

그룹group 박테리오파지의 처리량Throughput of bacteriophage 마우스 수Number of mice 대조군Control group 비강 내 PBS+SM 버퍼 1회 투여/30㎕One dose of PBS + SM buffer in nasal cavity / 30 μl n=5n = 5 녹농균 접종군Pseudomonas aeruginosa 비강 내 녹농균+SM 버퍼 주입:
1 X 109 CFU/ml 1회 투여/30㎕Nasal pseudomonas aeruginosa + SM buffer injection:
1 X 10 9 CFU / ml once administration / 30 μl n=5n = 5 PBS+박테리오파지 접종군PBS + bacteriophage inoculation group 비강 내 박테리오파지 1 X 1010 PFU/ml 1회 투여/30㎕Intranasal bacteriophage 1 X 10 10 PFU / ml once-dose / 30 μl n=5n = 5 녹농균+박테리오파지 접종군-1Pseudomonas aeruginosa + bacteriophage inoculated group -1 MOI:10 비강 내 녹농균: 1 X 108 CFU/ml
박테리오파지: 1 X 1010 PFU/ml 1회 투여/30㎕MOI: 10 Pseudomonas aeruginosa: 1 X 10 8 CFU / ml
Bacteriophage: 1 X 10 10 PFU / ml once administration / 30 ㎕ n=5n = 5 녹농균+박테리오파지 접종군-2Pseudomonas aeruginosa + bacteriophage inoculation group -2 MOI:1 비강 내 녹농균: 1 X 108 CFU/ml
박테리오파지: 1 X 109 PFU/ml 1회 투여/30㎕MOI: 1 Pseudomonas aeruginosa: 1 X 10 8 CFU / ml
Bacteriophage: 1 x 10 9 PFU / ml once administration / 30 μl n=5n = 5 녹농균+박테리오파지 접종군-3Pseudomonas aeruginosa + bacteriophage inoculation group -3 MOI:0.1 비강 내 녹농균: 1 X 108 CFU/ml
박테리오파지: 1 X 108 PFU/ml 1회 투여/30㎕MOI: 0.1 Nasal pseudomonas: 1 X 10 8 CFU / ml
Bacteriophage: 1 X 10 8 PFU / ml once administration / 30 ㎕ n=5n = 5

녹농균만 접종한 경우와 비교할 때 박테리오파지 YMC11/02/R656 PAE BP를 함께 접종한 경우 마우스 생존율이 증가하고, 체중 변화량이 감소한 것을 확인할 수 있었으며, 특히 MOI 값이 증가할수록 마우스 생존율은 더욱 증가하는 것을 확인할 수 있었다. 더욱이, 마우스에 PBS 버퍼와 박테리오파지 YMC11/02/R656 PAE BP만을 주입한 경우 마우스가 사망하지 않았다(도 13). Compared with the case of inoculation with P. aeruginosa, inoculation of bacteriophage YMC11 / 02 / R656 PAE BP resulted in an increase in mouse survival rate and a decrease in body weight change, and it was confirmed that mouse survival rate was further increased with increasing MOI value I could. Furthermore, when mice were injected with only PBS buffer and bacteriophage YMC11 / 02 / R656 PAE BP, the mice did not die (Fig. 13).

이를 통하여 본 발명에 따른 박테리오파지 YMC11/02/R656 PAE BP는 카바페넴 내성 녹농균에 대하여 용균성을 갖되, 마우스의 생존에는 영향을 미치지 않는 것을 알 수 있었다.As a result, it was found that the bacteriophage YMC11 / 02 / R656 PAE BP according to the present invention has tolerance to carbapenem-resistant Pseudomonas aeruginosa but does not affect mouse survival.

실시예Example 9. 마우스의 폐 내 녹농균 감염에 대한 박테리오파지의  9. Bacteriophage to mouse pneumocyte infection in the lungs 용균능Drag force 검증 Verification

생후 7주된 암컷 B6 마우스 60마리를 3세트로 준비하고, 각 마우스에 졸레틸(30mg/kg)과 롬푼(10mg/kg)으로 마취시킨 뒤, 각 마우스의 코를 통해 카바페넴 내성 녹농균 1 X 109 CFU/ml (620nm=0.6)을 접종하여 폐 감염을 유도하고, 30분 후 하기 표 4와 같이 준비된 박테리오파지 YMC11/02/R656 PAE BP를 접종하였다. 1일, 3일 및 5일 후 부검하여 폐 조직을 HE 염색하여 현미경으로 관찰하고, 병증 심각도(histological score)를 점수 매기고, 폐 조직 내 녹농균의 수를 카운팅하였다. Three sets of female B6 mice (7 weeks old) were prepared in three sets. Each mouse was anesthetized with zoletyl (30 mg / kg) and lompun (10 mg / kg) and then administered with carbapenem resistant Pseudomonas aeruginosa 1 X 10 9 CFU / ml (620 nm = 0.6) were inoculated to induce pulmonary infection. After 30 minutes, the prepared bacteriophage YMC11 / 02 / R656 PAE BP was inoculated as shown in Table 4 below. After 1 day, 3 days and 5 days, the lung tissue was autopsied, stained with HE, observed with a microscope, scored for histological score, and counted in the lung tissue.

그룹group 박테리오파지의 처리량Throughput of bacteriophage 마우스 수Number of mice 대조군Control group 코 속으로 PBS+SM 버퍼 1회 투여/30㎕In the nose, PBS + SM buffer was administered once / 30 μl n=5n = 5 녹농균 접종군Pseudomonas aeruginosa 코 속으로 녹농균+SM 버퍼 주입:
1 X 109 CFU/ml 1회 투여/30㎕Pseudomonas aeruginosa + SM buffer injection into the nose:
1 X 10 9 CFU / ml once administration / 30 μl n=5n = 5 PBS+박테리오파지 접종군PBS + bacteriophage inoculation group 코 속으로 박테리오파지 1 X 1010 PFU/ml 1회 투여/30㎕1 x 10 10 PFU / ml bacteriophage into the nose once / 30 μl n=5n = 5 녹농균+박테리오파지 접종군-1Pseudomonas aeruginosa + bacteriophage inoculated group -1 MOI:10 비강 내 녹농균: 1 X 108 CFU/ml
박테리오파지: 1 X 1010 PFU/ml 1회 투여/30㎕MOI: 10 Pseudomonas aeruginosa: 1 X 10 8 CFU / ml
Bacteriophage: 1 X 10 10 PFU / ml once administration / 30 ㎕ n=5n = 5

녹농균만 접종한 경우와 비교할 때 박테리오파지 YMC11/02/R656 PAE BP를 함께 접종한 경우 폐 조직의 치료 효과를 확인할 수 있었다. 녹농균 감염 그룹은 폐포 벽의 두꺼워짐과 호중구 침윤(neutrophil infiltration)이 매우 심각하게 관찰되었으나, 박테리오파지를 처리한 그룹은 매우 호전된 것을 볼 수 있었다(도 14, 도 15). 또한, 마우스의 폐에 감염된 녹농균은 박테리오파지 접종 5일 후 대부분 제거되는 것을 확인할 수 있었다(도 16). Compared with the case of inoculation with Pseudomonas aeruginosa, the treatment effect of lung tissue was confirmed when the bacteriophage YMC11 / 02 / R656 PAE BP was inoculated together. In the Pseudomonas aeruginosa infected group, thickening of the alveolar wall and neutrophil infiltration were observed very seriously, but the group treated with bacteriophage was found to be very improved (Fig. 14, Fig. 15). In addition, it was confirmed that P. aeruginosa infected with the mouse lung was mostly removed after 5 days of inoculation of the bacteriophage (Fig. 16).

이를 통하여 본 발명에 따른 박테리오파지 YMC11/02/R656 PAE BP는 카바페넴 내성 녹농균에 대하여 용균성을 갖는 것을 알 수 있다. Thus, it can be seen that the bacteriophage YMC11 / 02 / R656 PAE BP according to the present invention has a tolerance to carbapenem-resistant P. aeruginosa.

더욱이, 마우스에 PBS 버퍼와 박테리오파지 YMC11/02/R656 PAE BP만을 주입한 경우 대조군의 폐 조직과 비교하여 크게 다르지 않은 것을 볼 수 있는 바(도 14), 본 발명에 따른 박테리오파지 YMC11/02/R656 PAE BP는 마우스에 어떠한 부작용도 일으키지 않는 것을 알 수 있었다.In addition, when the mice were injected with only the PBS buffer and the bacteriophage YMC11 / 02 / R656 PAE BP, they were not significantly different from the lung tissues of the control group (Fig. 14). The bacteriophage YMC11 / 02 / R656 PAE BP did not cause any side effects on the mouse.

이상, 본 발명을 상기 실시 예를 중심으로 하여 설명하였으나 이는 예시에 지나지 아니하며, 본 발명은 본 발명의 기술분야에서 통상의 지식을 가진 자에게 자명한 다양한 변형 및 균등한 기타의 실시 예를 이하에 첨부한 청구범위 내에서 수행할 수 있다는 사실을 이해하여야 한다.While the present invention has been particularly shown and described with reference to exemplary embodiments thereof, it is clearly understood that the same is by way of illustration and example only and is not to be taken by way of limitation, It is to be understood that the invention may be practiced within the scope of the appended claims.

한국생명공학연구원Korea Biotechnology Research Institute KCTC18363PKCTC18363P 2015032320150323

<110> Industry-Academic Cooperation Foundation, Yonsei University <120> Lytic bacteriophage specific for Pseudomonas genus resistant to antibiotics <130> DPB154224 <160> 12 <170> KopatentIn 2.0 <210> 1 <211> 60919 <212> DNA <213> P. aeruginosa phage <400> 1 gccaggccac cgagccgacc gctctttaac aagtcagacc ccaccgcagt cccgacagcc 60 gcaggtcacc gcgactgagc gacggtggat aaacacgact gctgatgccg ggtaatcccg 120 gccaactcaa cgccaggcgt cgcgctccct cagctcagaa catcgagcag atagcgcaaa 180 gcgggctgag ggttgcactg ctaacgctcc ctgctcgggc catgaattgg cgcattcctg 240 ggcacagcgg acaggcctcg caaaggcttg cggtgaacac aaccaatagg aggaaacagc 300 ccatgaagca ctaagcccag ccgacgacac gggtcggcaa tccgcgcgta cgtgccctac 360 tcaacgggcc gccgggctgc actcaagcgc ggagtaacac tgatacccca tgaccagcgc 420 tgtatgccga ttgaaggcgt tgcgagggaa gcccaaggcc aaacacatca agtccgagct 480 gctatcggca gtggtgagga cacaccaccc gcgggttgta gaagcccagc aggcgaacgc 540 aggagtggga acgaaccccg acaaggagaa gcgaccgaga cgacccgatt tctcagatgc 600 ccttcgcaag aggggcatcg aagaagtcaa cacgcactgg aaggcaagac gatgaaccaa 660 gaccaggcct atctgctgag ccagccatat tgcttccaaa tgggttttca agactttcgc 720 ggtggcgagc aatttgacag caggcggaat gccgaatggc aacgcggctg gcgttgggcg 780 aacgcaaaaa gcgtgtctcg ctcgaaataa ccaccccgcc cggttcgccg gggcatcacc 840 gaggaaagga catgatgatt ctaggcagcg ccaggcgacg cgtgcgcgcc aagcttcggg 900 cggagcggcg tgaagccgtt gtggaggccg ctatcgccgc attcacgact atcgagcgga 960 accgatttgt aaacgacgag agtgcggcgc tctacgacgc tgtcatcgcc cttctcaata 1020 cgccgccctg ccggtagcag ggcatcacca gacccaacac acccagcgat aagcgggaag 1080 agaggaatcc atggccgtac ttgtgatcct tgatgcgaat ccaaatgagc ccgaaggctg 1140 gcgatttcta aaagccgacg agtacgacgg agcggggcac tggaacgata acaggacgtt 1200 cccaactact gatgatgccg atgcttggat tcaaaagcat gcgcgcaacg gctggtacac 1260 gttgattgtc ggtgaagacg acgagtagca agccgcccgc gcctgccgga ctccccaacg 1320 caggcccgat ccacctggct ccccatcgcc aggctgtatc ggagagtggt ctgagcgcat 1380 agctgtagcg taggtgcgtc acagacgact gggttggacg gtgatgggtt ggccttatgc 1440 catcgaagct tccagctacg ccggagatca gcaccggcca gaccactccc ccatacagcc 1500 aatcacaagc cccaagggca agagaggaat ccatgccatc acttggcgag ttcgcagcgc 1560 tgttcgtggt gctgtttctg actatgtatt ggtgaggtga gagatgagtg agtggatcaa 1620 gtgcagtgac cgtatgccgg agcactcaga tgaagtcatg gtttgccgaa agtggccggg 1680 ccaggactgt ttcgctcccg agttcgaccg ctgggtatct gacgaaggct cggatgaagg 1740 cggtttctgg atgctggccg aggattcttg ccagcgcatc gaaacctgtg ctgatggacc 1800 gggccatgta gaacggcctg aaaccaccca ctggatgccc ctacccgaac caccgcaaga 1860 cgcctgacag gcaggagaac agatgatgaa gcacacgcaa gggccgtgga gcactaggtt 1920 agttcgacac gttggactca aagcaggttc gcatgtccat gttctaacgg accgcgaagg 1980 tttcaacatc gcgctgatct cttcgtggat agacaacaca gatacagcag aagaagcaat 2040 cgcaaattca cgcctgatcg aagccgcgcc cgagctgctg gaggtcctgg tcgctctggt 2100 tgagtgcgag caaacgacac cagagctttg ggaagcagcc cgagccgcaa tcgcaaaggc 2160 caccgcctaa cgcgcccttg cgcatacaca cactggaggc gacatgagcg agtggatcag 2220 tctcaaaaag gagcgtccgg gcgatgagca tgatgggcgc tacctgatta tttacacatg 2280 gagcagcgca aggctcaact tcatcgttga ggccgacatc tggcttggca gtcaattcga 2340 attttgggga gacaaggtat cccactggat gttgctacct gagccgccag acgcctgact 2400 tccccggcaa ggacgccagc cttcaatggg gatgatgcgg agtgatgatc cgcagagagg 2460 caatctcgct cggaacaatt tgccaagcac tgacaatggt cagccgtttt agccgagcca 2520 gccggacata tccccggcca tccccaccct acccctctta gcccggcaag tccgggcatt 2580 ttttcgcctg tatgcgcatg cgccctgaac gaatcgtctt cgggagcggg gcttatgacg 2640 aggcctacgt ctcttagggc gcagccgcat gcacgcgaac gcgaggtgaa atatgaacac 2700 cgcatttcga tgcgcccagt cgttacatga cgacgcgact cctgacgaca cccctcccgc 2760 cgctaactcc gatgagttct gcgactgggc agaacacgca gtcaacgatc tgcggtgcgg 2820 catggacgtg aagatcgaaa ccatgcgcga gcgtgtcgtg gtattcgcca gcacgctgac 2880 cgagcgggta caggccgaac tgctgaagct cgtccaggcc gacgaagaat gctggctggc 2940 tcagatgttc caggccgccg aagacgagtt cacctctacc gcccgcgagt gcgcggcaaa 3000 ccttgagcat caccagggaa tcactgaacg catcgcgctc ggactcctga agccgcacgc 3060 ggacctggtg ctggaaatga tcgcagagca gaacatggag gatgcagcat gagcattgac 3120 tggaccaagg cacctgaagg cacaacgcac taccacatag gtgaagacat aaatccttgg 3180 cgaaaaatcg aaggtactgt tgcgtacgag cactacagag gcaaatggct cagggtcaac 3240 agtttcaacg aaggatgcat gcctggctat tacgtaccta ttccgcaaga gacctgggac 3300 ggccagggac tgccgccggt tgggacggtg tgtgaagtca agcaccgaga tataggctgg 3360 gttagatgcg agattgttgc ccacaaatcc tttagttgtg gtggccttac ccatgcaatc 3420 gcatggatag acgaaaacac ccttgatcaa tctcaagggt tgcgattccg ccaactccgc 3480 acccccgagc agatcgccgc cgaggagcgg gagaaggcag tcggtgatat ggctatgtca 3540 attcaaggag ttccatatca gtaccctacg ctttacgcgc tatttgacgc cggctaccgc 3600 cgccaggagg aagggaaatg acaaccccta tcgtgcaatc gatcagtgat gagcaattgg 3660 cggagttgga agagtactgc cacaagaggg cattcgtctg ttgtggcaat ttcaaatccg 3720 gggccgaata catgggcgcg cgcgaggaag tctgctgtaa cgagccagtg ttgacggatg 3780 taaatatcaa cactccagca gaggagatac ttggcctgat cgctcgcctg cgcgctgctg 3840 aggcttatgc taagcgctgg cgtcatgcgc ggaacatcct gaccgtcgag gcgattgagt 3900 cagctcaatc tgattacatc aacttcggtt tgccgcctgc tgaaagcgaa agcatccgcg 3960 cagataaggc catcgacgcc gcgatggagt gcacgctatg accatcacca tagacctgaa 4020 agaggccgcc aagacaacgt tcttcgcggc ctttttcttg ggcagcatcc tggccttcgc 4080 cgtggcgttt gtggaggtgg cggggctatg agcggaaaga aagcagctaa gcgcgcacat 4140 gctgtagcga tgcgtgccgc aaagcttcgc cgggacggct gtagcctgtc cgcaatatcg 4200 gaggctacga gcatcccgcg cgagcaaatt gaatctcgta taaagcttgg cgaacgtctg 4260 ctacagcttg tcgaaacgga gtttgggcaa tgagcacccg ccgcacggcc atctggctag 4320 gcagcctctt cggaggcctg ctgtacctct tcatcctggc agccggcccg atctggggcg 4380 gcatcatcac cgcagaagct acgcacctgt ccgcagcagg cccatagggg ataactgcgg 4440 cttccccagc gggcggtggg cggcatgaag aaaacacccg cagcagcggc ttctagcgca 4500 acgctattca tcccgcagag gtgacgctgc cgagtggcgc cgtaagcgcc tttcaccttc 4560 tacctggaga acgatatgaa catctacgaa tgcgaacgcc ttgcgcgtga tcttggctac 4620 gatagagcga agttcacggc aatcttcccg gccggcccat tcgaatgcca gtggctggac 4680 gcctacatgg gaatcttcaa ggtcgacgct gacgggatgc gtgacggctt cgtcatggtc 4740 aaggaaatgg ctgagatgtt cccgaacttg gaatgcattg acctgcgcgt cgaagacgac 4800 gtctaacact cccttcactg gctgcgcatg cgcggcgagg atcattcatg tccgcagaaa 4860 accaactggt cgaagtacca gccaaagaaa ccgctctgca agtctactcg gcagacaatg 4920 gcctggatcc attcctggcc aagattcgcg aagagatcga cggcttcgtg ccggatgtga 4980 ccactcgcaa gggccgagag gcaatcgctt ccatcgccta caaggtagcc cgctccaaga 5040 cggcgctgga caacgtgggc aaggaattgg tcgctgagct gaaggaggtc ccgaagaaga 5100 tcgatgccga gcgtaagcgg atgcgcgatc tgttggattc ctggcaggcc gaagtgcgca 5160 gtccgttgac cgagtgggaa gaggctgaag cggcgcgggt tgcgcgtcat cagggcgaga 5220 tcgacaagat aaaccttcgc ctggaatgcc gcgatctgga ctctaatgaa ctcaaagcca 5280 acatcgcttg gttggaaggc ctggccataa gtgaagcctg ggaagagttc gaggcagagg 5340 ctgctcgcgc caaagataag gctttgatcg ctctccgaga agccctggtt gcccgtgaga 5400 agttcgaagc cgagcaggcc gaactggaac gcctgcgcgc cgaagcagca gcacgccagc 5460 agaaagagcg cgaggagcgc attgcccgcg aagcagcaga gcaggcacgg cgtcaggaag 5520 aggccaaggc ccaggcagaa cgcgacgccg cagtacgccg tgaagccgaa gcacaggccg 5580 cagcagagcg ccgcgaactt gaacttaagc ttgccgccga gcgcgccgaa cgcgaagcca 5640 ttgaagccaa gcagcgcgca gaacaagcag agcgtgatgc gcaacgtcgc gctgaagaag 5700 ccgcagcggc agaacgcaaa cggcaggccg atgagcaggc ccgcatcgaa cgcgaggctg 5760 ctgcacgcga agccgacaag gcgcacaaga aagccatcaa caacgaagcg ctggcggctc 5820 ttatcgccgg tggcatgccc gaggaatgcg ccaagcaggc gatcaccctg atcgctcagc 5880 gcaaggttcc tcacatcacg atcaactatt gaggttcaca tgggaactgc actaacaccg 5940 ctcctgacga agttcgccac gcgctacgag atgggtacaa cgcctgaaga agtggcgaac 6000 acgctcaagc agacctgttt caagggccag gtcaatgatt cgcagatggt cgccctgctg 6060 atcgtggcag accagtacaa actgaacccc ttcaccaagg agttgtacgc attccccgac 6120 aagaacaacg gcatcgtgcc ggttgttggt gtggatggct gggctcggat catcaacgag 6180 aacccacagt tcgatggcat ggaattctca atggaccagc agggaaccga atgcacctgc 6240 aagatctatc ggaaggaccg cagccatgcc atcagcgcga ctgagtacat ggccgagtgc 6300 aagcggaaca cccagccttg gcagtcccat ccgcgccgga tgcttcgcca caaggcaatg 6360 attcagtgcg cacgcctcgc gttcgggttc gccggcatat acgaccagga cgaggccgag 6420 cggatcgttg aacgagacgt cactcccgca gaacagtacg aggacgtcag cgaggcggtc 6480 tgcctcatca aggactcccc aacaatggaa gacttgcagt cagcattcag caatgcctgg 6540 aaagcctaca agacaaaggg cgcgcgcgac cagcttacgg cggccaagga ccagcggaag 6600 aaagaactgc tggacgcccc tatcgacgtt gaattcgagg agaccggcga tgatcgagca 6660 gcgtagtgat gaatggttcg cacagcgcct ggggcgggtg acggccagca aggtcaagga 6720 tgtgatggca aaggggcgca gtggcgcccc ttctgctacc cgccagaact acatgatgca 6780 gctcctgtgc gagcgcctga ccggcaagcg cgaggaagga ttcaccagcg ccgcaatgca 6840 gcgtggtacc gaactggagc cgattgctcg ctcggcctac gagttcaatg caggcgtaat 6900 gacgatcgaa acaggcctga tcatccatcc gcgaatcgat ggatttggcg cgtcgccaga 6960 tggcctcgcg ggggagcatg ggctcgtcga gattaaatgc ccgtctaccg caacccacat 7020 ctacacgatg cagtcgggca agcacgaccc acagtacgag tggcagatgc tcgcccaaat 7080 gtcatgcagc ggccgcgagt gggtcgactt cgtgagcttc gacgaccgtc tgcctgatga 7140 attgcagtac gtgtgcttcc gctaccaccg cgacgaggaa cgcattcgcg agatggagtc 7200 cgaagttaaa gcgttcctgg aagagttggc agagcttgaa catcagatgc gagagcgcat 7260 gaggaaagca gcatgagagg tgttaacaaa gtcattctgg ttggtaacgt cggtggtgac 7320 ccggaaaccc gctacatgcc caacggcaat gcggtgacca acatcaccct cgccaccagc 7380 gagagctgga aggacaagca gaccggccag caacaggaac gcgccgagtt ccaccgcgtg 7440 gtgttcttcg gtcgcctggc ggagatcgcc ggcgagtacc tgcgcaaggg ttcccaggtc 7500 tacgtcgaag gcagcctgcg cacccgcaag tggcaggctc aggacggcca ggaccgatac 7560 accaccgagg taatcgtcga catgcacgga cagatgcaga tgcttggcgc caagcctgga 7620 aatgaccagg cggctcagag caggccgtct cagcaggcac cgcagcagcg cccacaggtt 7680 gcgcaggatt acgacagctt cgacgacgat atcccgttct aaatcaacaa gttacgcgaa 7740 attaaaggcc ctgttgaggg ccttttcttt tgcccggaga aagccatgga aaccgacatt 7800 cccgagattc ttagcgacct gagaataggc gctgatgcgt ggtccggcgt gcaagagccg 7860 gttgcccatg cgctgactca cgatgacatt caagacgcag ttgctgagta cctggcatcg 7920 ggaggggtca tcacgaatat ccccgctggc gtctcttcaa atcagccggt cacgttcaat 7980 agccgcatta ccggagcatc taccggaatg gagcgagagc agcagaagcg tgttcaggcc 8040 aagcgcacgg caaaggacat cgaatactgc cagacgctcg aagacctagt gatcctagat 8100 tgcggtcgat gggagatagg ccctgccatg gggataagcg atcacaccgt acagcgactg 8160 cttcgcacct atttctccac ccgcgccgag ttcgacaagt ggagggcatc cggacatggg 8220 aaatcgacgc tcataaacgg cgagaaacca tgctcgaagt gcaagacggt caaacctcta 8280 tctgagtact actcgaatcc gagcaagaag gacggccatt gcagcgaatg taaggcctgt 8340 gaaaacgcgc ggaggcgagc agcaaatgca aagcaagcgg cttgagttcc ccgaatcggc 8400 agaagaatac cgcgagggcg tcgacgcacg cgaccgcggc gaacgtctcc aggcctgccc 8460 ctacggactg cacatgctct atgagcggtc actttggcta gcaggacacc acgacagaga 8520 catgggcata gccccgaggg tagcagcatg agcctgcacg aacacggctg tttcgccgac 8580 agctaccagg tccgacatat caacgcgcag tgcgtcgtcg ggaaggtctt ccggcacaag 8640 ccgactaatc gcagatacat cgctgttctc gaagccggcg gatcagttga gcttcaagag 8700 accagcgggc acagcacgta cacatcaatc gaagcgctcg gcaatgccga ggtgtgggag 8760 gccgttaaat gagcatggaa atgaacaaag cgctggacct tctgcgcgaa atccgcccga 8820 gcattccgaa ggaagtgcta gagctttggt gcaaggaccg cgatgcattc atagcatcgc 8880 atcctgcggc agagcaggca ggcggggatg agcgcgcggc gtttgaggct gcttttgctg 8940 caatgggtag gccggtatgt cgtgctgatt acgaccaaga cgcctacgga accccattcg 9000 atgacggcgg atggactggc tggcaagccc gcgccgccct ggcgcaaccc tccccggcgc 9060 aggccgagca ggcagagccg gagcggccgg aggttgtggc gtggcaatac cgcgtcaccg 9120 caggcccgca aactggctgg agtctctggc acccaggaaa aggcgaggag ttcgaacgct 9180 cctacaccgt cgaacgccgg ccgcttatga ccgtcgccca gtacgaccgc atcgtcgggg 9240 agctgcgggc ggtgatcgcc caactccgcc agcacaagaa cgattacatg gattccggcc 9300 aggaaactta ccgagccttg cagaacgaaa tccgggagcg ggaagcggaa attgctcgtc 9360 ttgatggtct ggtttcgggc cgcacggcag agcgcgacgc cgctaatgct cgcctgcacg 9420 aagtagcaac agcctgcgca acggcagagc aagagcgcga cgccgccctg gccagggtcg 9480 cggagttgga gaggcaggag ccggtggcat ggatgcacga tcagccaaac cgcgtcgatg 9540 tcatccatcg agacgtcaag gatctgctac agcgcgtgcc gggcagtagt agaggaatcc 9600 atcgcccact cgatgtcagc gagcattaca cgattccact ctacgccgcc cctgtagccc 9660 aggctcagca cagcgtgccg gaggggtggg tgcaatcact gccgctaaag gatcaccagc 9720 cttgcaagcc gaacgaggat agagcgaacg gttacacaat cccgatctat tcaaggccgg 9780 ttcttgttga ggaagccttg cgtaagttac gtgctgtcct ctgcgaccca attggaaacg 9840 ttgtcattga cggcagtgat ggtgaccgag aagaggtaca gcgagcgctc ggtatgctcg 9900 ccgccgcgcc cggcaaggag gggaacgatg actgaatggc gcgaagtggt tggttatgaa 9960 ggactatacc gagtatcaga gcatggcgaa gtcatcgggg ttatacgcaa aaagatcaaa 10020 aagcaattcc ccaatactag cggatacatg tcagtaggtc tgtgcgccaa tggcaggcag 10080 aagaacacca cggtccacaa aattgtggcc ttggcgttcc tagataaggc cttcgagtcg 10140 ctagaagtaa atcacataga cggagataag ctaaataatc atcactcaaa tctagaatgg 10200 gttacgcgct tggaaaatct aaatcatgca aaaaagatgg ggcttcttag agagtccacc 10260 aaggtagtcg caatgcccat agacggctcg gttggatatt tcttcgtatc catcaatcaa 10320 gccgttaaga gtggatttaa taacggaaac atttacaact ccataaacgg gaaatcccca 10380 aatcacaaag gcttcaattg ggcgaaagtg cctagtgaaa tgcagatagg tgaacagcca 10440 tgaccgaaga agaacatgat gccaagctgc gcgccgaggc ccaggcgctc agggaggaag 10500 tcgcgcgcgg aaaccggatt acgttggcca tggcgctgga tatcgctgcg gtaggtgtag 10560 cacttgggat tcccggagag caacaggaag gtggaactgg tgaattcatc gaggccatcc 10620 aaagccttca gaaggaactg gaagccctgc gcgcacgggt ggtggttccg gatgggtacg 10680 cgctcatgcc gctggaacca tcccccgaaa tgcgtcttgc gagccaccgg tacaagcgca 10740 agaacaaagt ctcgaccgga cctggattct ggcgcgcaat ggccgaggct gctccgcgcc 10800 tcaacggcct gacggtcagc gaggggctgt tgaggctggc cttggagttc attatggcaa 10860 ctaactgcca gggctctatc ccgcttgggc tgattgaaga acttcgcgcc ctgctcaacc 10920 aggacaagga gaacggcgac catgctgcat gagccggagg agtaccgatt gttcagtcta 10980 tggatgctgg tcttcatggc catcggctgg tttggtggct ggatacacgc ccattacacc 11040 gtagccgaag aatgccggaa gctcggcaag ttctacgtcg gcaagaccgt attcgagtgc 11100 aaggcgatca ccgaggaaga caaggagaac ggcaatggct aaacactatc ctcttgaggt 11160 gcagagcgtc ggcagcgaca cctacatcgc aatgagcaag ggacaccacg acctcgaagt 11220 gttcatggcc gaggccgtca aggagtgccc gggtcggttc ttgggcggcc cgcagcacaa 11280 gtggtgcaag acggttccgg accgctcggg cgagtttgca catcggtatg tgttcgtcga 11340 ggaaggcacg ccaggcgcat ggccggcgac ctactgctgg gaattcggcg aggactggaa 11400 acgctggaat gggattggcg agcagcaggc atagccaccc atcgccaacc actgtacgca 11460 ccgatgccgg aatcccggca tcgcttacag gccgccttag caccagcctg aaacccgcat 11520 ggttactggg tttccgcgct taaacacagc tacttggcac caccttacag gccaccccaa 11580 accaacgaat ccgcccccgg aggaccaacc gtggacaacg aaaacgaaac cctggtcgca 11640 gtgatagtca tcgttctctt cgtcctggga gtcttccggg ttgtcgggga cttccagaac 11700 ctatacgagc agacagaaca gaaaggacag gagttgagca gatggagcaa gaattgaagc 11760 catgccccta ttgccgaggc tatgacctag agcgtcgctg gtgtcacgtt tgcaatggca 11820 gtggcgtcgt tgatgtcaag gctcaacagc gagagcgcgc agagattgta aaggcgctgc 11880 gcgaagccgg aattgaagtg agggactgac cgtgcctgac atgagagaag attttgaaga 11940 ccgcttcccg atccctgaag gtatcgagtg gcgtgacacc gattacttcc cgatgcagac 12000 cgataacgtc cacgtatacg tggctcttgc cggagtcgct gcgcgctaca cgtcgatgtg 12060 gcaagcctgg caagccagcc gcgcggctct gagggtggag ttgccggcaa aacgctcata 12120 cagcatgtat gcaacgaagc atgaatgtca tgcgttcaac gatgcgatag agaaggctaa 12180 cgaagccctc cagcaagccg gaatcgaggt ggcgaaatga gctacagcgt ggagaaagtc 12240 atgcgcgtct atgacgacaa agaaggcgtg tacatcgagg tcagacagca cccggatgca 12300 ccggacagcg gcctggaaat ccataccaca ggaaaccagg cctgcatcga ctggtacggc 12360 gagcagcgaa tcgtgctgaa cagccgggag cacgctcttg ccctggcaag ggccatcacc 12420 gaaatggcgg agatgatccc atgaccgaag acaagccgga atcgaggtga agcaatgagc 12480 gactatcgag tttggtgccc tgactacggc caggaagaag aagacgcgat gcacatccgt 12540 gattcgtacg accatgctgc cgcagcatgt aactgggccg agcaatatga gcggagaaat 12600 gctgactaca acatcgccga tggcgggtgc gtgacggtaa tggtccatcg cctcggaggg 12660 gatacgcaaa ccttcgcggt atctggatat gcacggccaa tctattccgc aaccgctatc 12720 taggagcaac catgagccga ctgaccgccg agcaagcgcg agatatagct cgcgaacaag 12780 accctgcgtt cgccgtagat accatccttg caggcatcgc aaaatcagcc gccgaaggca 12840 agtacgtgta caccacccgt gactatgggt tcggcaccag cacctactgc aacgaatgcg 12900 attacccgaa gctctgcatc gcgatcctga aggaactgcg cgggctcggt tacgtctgcg 12960 ctgtgcgagc cgaagaacgc ctgttcgttg acctgtggct cgaagtgaaa tggggagaaa 13020 agacatgacc gaccacgcag agctgcggag gctggctaag gcggcaacgc ctgggccgtg 13080 gagttgcaat cgccactggg caattgtggg aggaccaact cttgagttca cgaacggtgc 13140 agcgcagcag cagatagcca tggcctgcca gcaaagctgg atgcgtgaag aagaactgcg 13200 caacaacgcc gcattcatgg ccgcagccaa ccccaagacc atcctcgccc tgctggacga 13260 gatcgacggc ttgcttgctc agcatggccg cgatagctcc gaacttaggg cgctctgcca 13320 agcacgcgat gatgctagga aagagcggga caggctcaag gcggagaacg aggcgctgcg 13380 gggagcgcta caggcagtag tggatgatcc aacctggcgc agcaacgaca acaccctgtg 13440 gccgaagatc atcaaagcaa tgaacccagc cgggcgccac tagctctccc tgagctaacc 13500 cggctgggcg ttcaaatcct accagaaggc ctgaccgagc agttaacccc catattgccc 13560 gatgcgggcg ccctgcccgg ccaagcctcc acgaattcta accgccaacc cgatgccgtt 13620 gatcggccaa ggtctcgcta tgtctttgat ttcagttgag gcggccgccg gcattctcgg 13680 cgtgagccgc aggaccgcgt accgctacgc ggacgaaaag ctgatcccgg tggtcaggtt 13740 caaaaagaca atccgggttc acaaggaaaa gctcgaacag atgcttgaag aggaagccgc 13800 tgctagcatg cgcgacgcgg tcggcgtacc ggaggaagta tgccgtacaa gagaaacgac 13860 tccgcctact ggtggatctc tttcaaatca gcaacaggaa agcttgttag acgctcttct 13920 ggaactgccg actactcggc ggcgaaagca ctagagcaac aggagcgcgc gaaagcgtgg 13980 aaggaaaagg aaatgggcgt gaatccgccc aggacctttg aggaggtgat cattccgtac 14040 ctgcagcacg ctcgccagca tcagcgcagc tacgaaacga ccgtgcaccg cataaagccg 14100 ctgcgcgagt attttgccgg acgcgtggtc aacgatctag ggggccagga catacgggga 14160 tacggttcgc acagattgga tgccggcgca tccccggcaa ccattaaccg cgaactcgct 14220 gccctctccg cggctatcaa ccactgcaac accgaactgg agtgggccct tcctaacccg 14280 gtgaaggggc ggaagatgcg cgaggccgag gggcgtgatc gttggctgac cagggcggag 14340 gtcgaggccc tgtgccgcgc cgcgcgcgtc cagaagtttg gcccgatgct cgaggatttc 14400 atccgcctag cggtaaacac cggatgccgg cgggaggaaa tgcttggcct ggagtggcgc 14460 agagtggatt tcgccaatcg actgatctac ttggaggcat cccacacgaa ggcaggtaag 14520 cgccggagca tcccgatcaa cgaaggggcg atggcagcac taaagcgacg aatggcattc 14580 aggtccgaga acagcccgga atgcccctgg gtctttgcgc gcgctaacgg tgatcgagtg 14640 gtatcgcttt cagccggatt caagcaggcc tgccaggcag cgaagattgt ggactttacg 14700 attcacgacc tgcgccacac ctgcgcggca tggctggtca gcgccggcgt tccgttggcg 14760 gatgtacggg atctgctcgg acactcgaca gtcgcgatga ctgagcgata tgcccatctt 14820 gctccggcca gggtaaggga tgctgttggg gttcttgatc aagtccgtga aagccgaatt 14880 tcacgttctg ttcacgctga taatccagcg catctacatg gagggccgct gaagctcgta 14940 aacacttgat ttagaaggtg gtgcggacgg agagactcga actctcacgc cttgcggcgc 15000 tggaacctaa atcctgtctc gcacctcaga agcgcttata ttacaacagt ttacgccgac 15060 cgcaatcact taaactgtgc caatcgtgaa attccttttc acgttttcca tttccgcgct 15120 tcacgtttcc gtcacggcca gcattcagcg gtccgactcg taagccgcaa caccgctacc 15180 gacagagcgc cactcatcct gcggcatgcg cgaatcacag atgaatacct cgacctcccc 15240 gccttctttc ggctccgcag gccgaatagc agcatgccgg agaatcgtct ccatgtccgg 15300 cacgtagctg ctctccgagc cgtggaacga ccagatgccg aacttgccag cgctgcccac 15360 ctggtggtcg agcttcaccg accagccctt gaatcgaatc accagcatca ccgagctccg 15420 taggaaaagg ccgtagtcta ctcctaatcc tgacaggcct gattcgcagc caggagctgc 15480 gcctcgtaac cgatccgctg caagcgttcg gcgagcaacg cgcggacctt ggtctgcaag 15540 tcgtcgcctt ttcgcagccc agtagttgcc caagccggca cctccaccgc cggcacccgg 15600 cacggcaccg ccactggcac ttctacgcgc accgtgcgcg gctcggcttc ctgcctggcg 15660 gcgcatcccg ccagcgcgac cgcaacccac aatagagcaa aacctgattc acctctcatt 15720 gcccttcctc gacttgatat ttcggtcgtt tagctgtcta tactggaaat gtcacttgac 15780 atgcccaata tggacgggat aatcgcggtc caccggggga atcctgtgga taacttgtgt 15840 aagccagagg aggcgccatg aaaccagtcc aattccttct cagagggtat gcggagcaca 15900 aggatggcgt atggcaagcg ttctgcatcg atctgtgtct ggcagtacag ggtgagtctc 15960 gtgaagaggt gatccgtaaa ctccacgagc aaacctacga ttacctgaaa gacatcttcg 16020 agggtgaaga ctacccatac gccgctcagc tcctcgcccg caaagcaccg ctggtgcaac 16080 gcctgaagta tcactaccta gcatacaggg agcaggtcag ccgactgcgc gatgtgttca 16140 ccttcaaaga cgccatgcct cttaagctgg cgtaaatggc aaggctccac cccgtcacat 16200 gcaaacaggt caaggcagct ctaaaagcga tggggttcga gccaaggcca agaacgggaa 16260 catctcacga aaagtgggtg aagactgcgg gtagcaaccg atggatagta acagtcgatt 16320 gccccaaatc tcccttcagc aatgacctga tcgcctccat ggccagacag gctggaatgt 16380 cgacaaaggc attccatagg aagtgctgcg aattctagcc ccgccatcgc ggggcttttt 16440 acaatcccag ttcccgatca atcacctgtt cagtcgcacc acactgctcg ccggcggtgc 16500 gatcacgcag cagacggttg gcggcggaat actgctcggc ggcctgctgc cgcccctgct 16560 ccagcgcatg ggctgcctcc ctggcgcgct gctcaccagc ctgacgcagc gcggcaatct 16620 gcccgccctg ctccactact gcggcctcca ggctcccacg agcggaacgg caggctgcca 16680 gatccgcctg cgcggcatcc aactgcggcc ggtagtgccg cgctccgatc cagacaccgc 16740 cggcggtgcc gaggccgacc agcagcaggc aggccagcgc gaccgataaa gcgcgagcgg 16800 agatcacgac agcggctcca ggaacagcgc gcgctccgcc gctcgacgct tgaccagacc 16860 ctccaagcgc ttaccacccg cattcaccca gcgagggaac tggtccgctg ctccctggta 16920 gtcccccttg ttcagcagct tgagcagcgt ggacgacgcc agattggccg cgccaaggtt 16980 gtacacgaag ctcatcaggg catcccactg gttctggttc agtggcactt tcaccagctt 17040 gtccatctcg ggctcgaagc gctgaatgtc gttcgacagc atccgctcgg cctgctcgac 17100 ggtgatcgtc atgtagcggg tgacgccccg cgtggtgccg tagccaatgg tccaaacgcc 17160 taccgagtcc tgataggcgg acaggcgcag gccctcgaag gatttgatga ggtctatgcc 17220 tcgttgggat gtacgcattt acgggtctcc aaagacgacg aagcccgctc aatggcgggc 17280 ttatcttcgt cgggaatgtg ttcgggtcag ctaccggtca ggatcaccaa cagcacggga 17340 gacgacagcc aggcggcggc tccacaggcg aggatcagca gactgacccc gatgcaaaaa 17400 ttcaggaaat gactcgttgg cattttgacc tccagccagt ctttaacctt cagcaagatt 17460 ggtctacgat tcacgtatgt tctgctcctt gtccttccca aggggtggaa ataaaaaccc 17520 ccggcacgct gtgaacgtcc gggggttttg cttttctgat tctgtcttta cttttctgta 17580 accctgcaag cgatctcgac catctccctg ttgaagcgag tcgagtcggc aagaatcacg 17640 ctgctgtcaa gcacggcaaa cctagtgaag cctgtgtatc caccatagct gttcttcgca 17700 ttcaccttgc cgcagatgga gtatttatct ggcggggctg caatcgaacg aacgccaatc 17760 aatccactga actttgcgga gtccgggtct ttcaagacct ctcgaacgga cgccattgca 17820 tgctcacgct gctggtcgtt cagctcaaac gatacggttt ttggctttgg ggcctgcacc 17880 ttgggagctg ggggtggcgg agtcgcacag ccgctcaatg ccgcaatgca caggacaata 17940 caggtcatgc ttttctggaa catttggatc ttccttccgt tgagaccgac gaaacatagc 18000 atgttgccat cccttcgacg ccttgacact gctgtacgcc tgaaccatag tctgcctgcc 18060 gctgcaaatt cagcggtcgg gcttggccgc ccgaatcggt aaggcgcaca gcgccgcagg 18120 gcgttttttt gtgccctcgc tttatggcgg gctgtgcgtg ggacaccttc gggtgtgccg 18180 ggagccttac ccccggtcgg ccaacccgcg tacagttcgc ctccctcttc ttggtcgcag 18240 agatggcgaa ctcccaaaca ggtaaggagt cctcatcatg caaaccgctc aagtaattcc 18300 cttccagttc gatgctcgcg aagtccgcac cctgctgatc gatgatcagc cttggttcgt 18360 agcggctgat gtttcttgcg ccttggaata ccgaattgcc ggtgacatga cgcgcaatct 18420 cgacgatgac gagaagggta cgcagattgt gcgtacccct ggcggcgatc aggaaatgct 18480 ggtcatcaac gagtctgggc tgtactcggc gatcctgcgc agccgcaagg ctgaggccaa 18540 gcgcttcaag aagtgggtaa ccgccgaggt acttcctgcg attcgcaagc atggtcgcta 18600 tgaggactcc agcaataaga tggcaaccct ggttggcgaa accatcggca ccgacggctt 18660 ccacatgctc ggctcgctga tcaagggcaa ggtagccgcc ctccccgtcg aagtccgccg 18720 ccgcgccacc gcgaaaatct ggtcacagac ccatgccgca ttcggggttc ggtctgccac 18780 agacatcccc gccaatcagt tggacgcggc ccgcaacttc gtcgccgcct acagcgttca 18840 cgaaggcgaa tggctgccga agcctgaaaa acgctgcggc accatgctca acgaccatca 18900 gctctacgac gtgtacttcg tttgccacca cttccagtac ctgttcgaaa tcttcaagcg 18960 gcacaacctc tactacttct tgaggcagca cggctcgcgc gcaggcgtag agatgatcga 19020 ccacttcaag gatggctaca tgggcgtctg gcagctcagg agggatttcg atggtgagtt 19080 tgatgccgta cagcggcggc tggggctcaa ccggtattct gggctcagca tccgctagtg 19140 attggctcga cgccggctcg agggccggcg ttcgggagga tctgcagcaa ctgctgctcg 19200 gtgatgggca tgtgagctcc agaaacgacg aagcccgcgc agggcgggct ttcgttcgtc 19260 gataggtgtt gtcaggctgg tagctgatcc ggcagaggat acctggcctt gatctcctcg 19320 accttggcca cccaggcgct gtagtccggc tcggtaccgg ccttgatagc gtcgaactcg 19380 gcctcggtct tgagcgggtc actctccagg cggtaggcat ttgcccgcgc gacggctgcg 19440 gcatcgtact cagcctgcca gcgttcttgc gcctgctgtt cagcggtctt taccttgctc 19500 cagtcgatca tcgcggtaac tccacaggtc catcggcatc gatcagcaac ggttcaggaa 19560 tgcgagcggc ggcacttgca tcatcagcca gcgggaaccg caggctcagt tccagccggt 19620 cggcacgtcg cactgcggga ccagcgaacc actctgatcc aatcgcctcg gccggcagtt 19680 cgccaccctc cggtaacggt gtgaagtcga acgcctggcc gttcacggtg agcacatcgc 19740 cagccctgct cagcgatagg cgttcgccgc tgcctggcag cggatagtac ggtgacaatg 19800 tgatgatcat cagtaccatc tcccaaacgc gatgtatccg ggcataacct cggctctatc 19860 aacaaatccg tgagaaatca gcgtcacaac agaagccgac ggagggttca tcgaaagcca 19920 tgcacgagct gttgcgccct ctctaaacgc cggaaccggt gaaacagatg gcgcagcaga 19980 aaacgcagca ggaaaataga gcgcagcaac gccccccgac tgaaacccac ccccggtcgc 20040 aacgctgcac accagagcgg tactgctaac gccagcgcat atctgagttc cgtccgcaaa 20100 ccgcacgaac tctccgttcg cgttgctccc gcgctggatc accgcaccgg tgggtacgcc 20160 gctcgcctgc gaaaccgtgc cgagaatact gtctcgagag tacagcgcgc ccgaactacc 20220 gagcgcttcg cggacagccg cactgccgag gccgagatcc ccccgcgctg ccgccgcatt 20280 tgcagagagc gcccagggct taatccccgc cagggttgcc ccccactggc tggcgatcag 20340 gttgaatcga tccgacaggt ccttgtcgta gcccaggatc ggcgccaccg cataggcctg 20400 gccgctggcc gtgctgccct ggtagttggg cttgatcgag atgaccgtcg aactggcgac 20460 gtttgtgacc tcgtaccaac gtccatcggg tccgcgaaat gcgtcgccga ctcgggcatt 20520 ggacgagaac tgtgtgccgg taccggtaac ggtcgggcta tttgcggtca ccgccacggt 20580 tccggttgag taccacgcca tagagttctc ctgctatgca atggccagaa gaggccatgg 20640 gaaaggtgtt cgtattgcgt cttgcccagg tccgccgact tgaacagttg ctacgactgt 20700 gtttcgggcc gaagtaacaa acccaatgga gcactctcca gtatcacctt ggggcggttg 20760 cgcctgtaca ttgaaatgac taaccagaaa atacccatca ttcccatgcg gccacggtgc 20820 agaccatgaa tgcagggtgt aatacccaag ataattgcca ttcgtgccgt aataattcag 20880 cagctgggta ccacttatga accgaacaag atccctatta ctgtcaaaca ccactctcga 20940 ctgattgtca aatatttgca tcccccatcc gccagttttc ggcatgaaca ccgcgcatgc 21000 cttccacttc cctcccagta cgacgccgct tgtatcttga aataccttca cgtagaagct 21060 gaaacccgtc cagttcccag ccgaaccagc atgctggaac atcgttatgt gatgcgaccc 21120 attagggcaa aagaaaacaa acggtgggag cgggctctgc accggagatg ggtacgagac 21180 gttgatgatc tgggcattag tggctggata ggttccagac gcaaccagat gcagacaagg 21240 gtggtcctga tcgattatca cctgaccggc attcccaaca aacttcgcac cgaaactcat 21300 gagaacatca ccgcatatag agtgtaattc gctgttacat caccggacca accaaacgta 21360 atagtcgagc cgctaatggt atgcctggga atccaagatc tagaatccgg cgtattgcag 21420 acgacaaaca tgacaccttt agaaccgtcg aacccaggga ccgtaactga aagtccctga 21480 ggaatgttcc ccaagtcccg acgatagacc atcctcaatg agtaattgtt gctgtcaaag 21540 agtattgagc cgccggctga acgtgttctc attccgtaac tcatacatca agattcccga 21600 tctggactcg aagcaccaag tttccgtcat acacttttat tgcctctgcc gtctggcgca 21660 taaaccctcc cgacgttgcg ctgttcattg tgaacgcgcc gcccttatcc aacttccaca 21720 gcggctcgcc gttggcaccg agggcggtcg actgaatcac gttgccgatc ttcgcgttgg 21780 tgatcgagcc gtcctggatc atcgcgttgt tgatgaacat ctggccgccg acgatcgaga 21840 ccggcgccac ggtctgcccg ctggaactgt tgaaccagag gaaccgatca gcctggaacg 21900 ccatggtcgt cacgctcgta ccgctgtcga acccaagctg gaacccggtg gcgtactgct 21960 gcccattggc atgggcctgg atcttcacgc tgtacatcgc cttcacgccc tgatccagtg 22020 acgctacaac gctctgcgtg gtctgaatcg cggccccgtt ggcgctcgtt tgcgcctgga 22080 cggtctctac acgcttcgcc tgcgcctcga tctcattcgc gcgcacgatg acctcggtgg 22140 ctgctcgagc aatggtgtcc caccccttca gtgcatccgc tttctctccg gtagccggct 22200 cccggcgcgc ggctgcttgc agcacgtcca ggctggaggc actggactga acaacaccgt 22260 cgagctcttc aatcgcggcc gcattctcag tcacgcgtaa cgcaagggca tcgaccgatt 22320 cgacgagctc gcccacatca gcccagtaaa cggggttcgg cggcggattg cccgcgggaa 22380 cgtcctggag ggcttgatag aacctgccgt tcaatcgaac gatctggccc ttctggtata 22440 ccgtgcccgc gtcgtagtac tgctccatca actggtcgac gttaccgccg atctgctcga 22500 tattttcgaa gaactgctcg cccagcgcgg actcgacgta ctcctttgtg atcagctcgt 22560 tgtactcgct cgcatccgtc gagctgatgc cgtcgaccca ggccgaccag gggccgacat 22620 tgccggtccg gtcgatcagc cgcccgcgga aggccaagcg agcgccggcc gccagcgagg 22680 tcagcgtgtg ggtatcggtc gggtacgcga acaagcccaa ggcagttgcg ttctgctcgc 22740 tgccgcccgg ggtaaccgac tgctggatct cggtgtaagc ggtgtccgcc gcgccactgg 22800 ccgggaatcc ccactccaga ccgatcttcc acggcccgct ggtggtacgc aggaacgcca 22860 gcgccggcgg cgcgccggtc ttgccgctga gttgggtcag gatcgaactc ttccagaccg 22920 acgtgatgtc gaaggccgac accgcacgca ctcgcgccag atagccacct gcgtagatgc 22980 cggtcacatc gacgctggtt gtgccggcac gcggcaggcg gatccagttg ccgctatcct 23040 tcttccactc gacgtcgtat gccaccgccc cttctacagc aggccaggcg atggtcatcg 23100 tgctgaccgc caacccctga tcgaactggt agtgcgaggt cagcgtgacg ctcgccggcg 23160 gcgccacggt ggtgatcggg ataacgctga tcggccggtt ctccaacttg gcaccagtgt 23220 cgatcgctga gaacttcccg ggctcgtact gcagcgcagt gatctcgaag acaccccgct 23280 ccggctggct gactttcatc acacggtaga gcggcaccgc caggtcgtcg gcatcgaggg 23340 tccagaccaa ttccggtagc ggggtctcgc tgtaggctgt cgtcacggtt accgcgcgcc 23400 cggcaaccga ctgcacggtt cgcgcctcag ccttaccgct gggcaggttc aggagcagcc 23460 ggtcgccagc ctttgcctgg gtatcgcgat ccaaggtgat cactcggcca gcaaccgcag 23520 aaacccgccc cccaatctcc cgtccagcca gcagcgcgtc agccaccgga atcacccatc 23580 ccggcagcgg aatcgccccg tccataccgg tacggaacgt taccgtgcga tcctggctgt 23640 tggttaggat cgcccatttt ccgcgccgct gggcctcact ctcgcgggtg cagccaatgg 23700 ctgccacctc gaccgggttg tcgccgtaac gccgctgcag gcgcttatcg gtggccacag 23760 ccacgtcggt gtcgtagttg ttcgccggat tgtcgtagct gaccaaggca cggctgtagc 23820 gagtgcgctc actggccgag ccgtagctga agcggccgtc gatgacattg gccctggtgt 23880 aggcgaaatc gacgtcggtg gcgcgcggga tatccgcctg gatcttcagt tggccctggg 23940 cccagtacgc cataccacgg tagatagcgg tgaggtcgcg cagcagctcc caggccccgg 24000 cgcggctttg caggttcagg ttgcaggtgt gtcgcggctc ctggccaccc ttcccatccg 24060 gcaccaactg gtcgcagtac tgggaaatcc ggtacatctc ccagcgatcg accatccaag 24120 ccttgatgcg tttacccaca ccgaagcgat cgttggtcac gatgtcgtag gtgtgccaga 24180 ccgggttgtc ggtccaggcc tgtttcatcg tgccgtccca gatgccgagg taggcccggg 24240 tctccggatc gtaattgctc ggcacttgga ccttccgccc gcggcagtcg actgtgacag 24300 ccggaatgtt gctgaactgc tctgcgctga actcgacgta cagcagggcc gtgttcgggt 24360 agcgcagctt cgcgtcgatc acctcggtgt agccggcgat cagcatggtg tcggcgatgc 24420 ggttgttgtt ctggttcggc gtcaggcggc ggacgcgcac ctgccagcca ttggtggccg 24480 ccggcaggtc gatccggcgg gaacgctcgt agcgggtggt ggtcttgcca tcgacggcct 24540 cgcgcagcac ctcctgatag gcgccgccgt cggtggccag atctacggca tattcgatcc 24600 ggtacccgcc gatgttgccg ttggtgtcct gctgctggag cgctggccag gcgaagcgca 24660 ggcgcactgc ggaaagctgg gtattgctca gcgagcgcac ccagggcgta tcgctgcgca 24720 actcgacgtt gacgctggtt tcgttctcaa cggcagggat gcccgggatg tagtcctggt 24780 ccaccgcccc cgcgcgccac tcccacttaa cgtttgggaa gttcaggtta ccgctcgggt 24840 ccatcagcgg ggtgttgtcg aggtagatgt cgcgctcgct cggaacgccg gcgaactcgc 24900 cctcgcccac ggcaagcagg atcttggcca tcgcgaccga gcgcaggctg tcgggtgcct 24960 cgaccggctg tttcggtttg ctactgccgc ccttgcggcc ggccaggtgc tggtgaactg 25020 cgcccatgct ttcctccggg catgaaaaag cccgcgcgag gcgggctgga aggttgtaca 25080 gcgtggatga aatgccagtg gcaaccaccc taccggggta gtagcgtcgt gccttcatgc 25140 aagggtttcc cgaccctgag cgtgccggcc cagggatcgg gaggcgccaa tgtcggcgcg 25200 gttaaagacc taggaggtca agatgagcga aaagcccgtt gtgtcaccct tccaactgag 25260 cgttatggcc gcactatcgg tggttggctc aattcttggg tcaacgaaca aaggggccat 25320 cgacaaggtg gttgagcata tcgagaccat caaatccaaa atgccagcag atgcttccct 25380 ccgcgacgga tcttctgagc accacctggc tcttgatgcc ttgatttcag ggctgagggc 25440 tgccagcaag atggatcaga tctaaaggat cggctcaagc ccaagagccg cctccatcct 25500 cgaaagccga cgctcgagca ggtcggcttt tctttccaac tcgtctgtaa gctctttcgg 25560 cagacacagg ccagtgacat caaccggcga gatcgttgcc tccgagacaa gcctttcgaa 25620 ctctgcacta ccaggctgcg gaagctctac gaccacatcc agcttatcga gtttcatcac 25680 actctcccgc ggcatagccg ctcatggttg gttgttacac cttgtcctcg gcgtaaatcg 25740 aagccgagat aatcgccccg ccccaccggc gcttcccgta gcagatcggc accgggttcc 25800 cgctggcggt ggtgtttctg gcgctgccga aggcgtagct gggcaagttc tccggcgccg 25860 cgctctgctt caggccctgt gcttgggggc tgagcatttg gatgacgccg ccggcaacca 25920 tccctatccc tgcaggcagc gcatacgggg ctatgacggg aaaagcgtag gaagcagcga 25980 tcagcacagc cccgactatc gtctgcacca acccgccacg cttccggcca cgcatgaccg 26040 gagcaatgcg aatttcctcg gcgcccccga actgcagctc atcttgggaa atgttccgtt 26100 tcccacggaa tacagcgaac tccatacctc gcaggtggga attggcgagg aagcgctcga 26160 ggcctggaat ctgcacgcac aaggccttga tcgcttccgc agtcgacccg actagcatac 26220 ggtactcccg gccgaactgc cggagcgcgc cgtagagttt gatggtggtc atcggagtgt 26280 ggtgcgctgc gatggtcatg tgtttctcca ggtaataaaa aaccgcccgg aggcggttct 26340 gcactgaaat cgataaacag tgggggtatc tacttctcta tccagtccag ttttccatgc 26400 atatagtgga ctgcactaag ccttcttttc accgagtctg cctttttctt ctccgcgtat 26460 ggtccgacca caattgtcga ttcagcactg gagaatattg gcaactgaag ttcttcgagc 26520 ttcgcaagat gcccatcaaa ctcctctccg ggcttacatg cgatattcac tgtccaccca 26580 tgagttagag gaggcggccc ctcgggagcc ggggttgctt ccacgtccgc gccgcagaat 26640 cgacacttga cggcggcaca cttaatagtt tctgcgcaat acggacatgg ccgagagtca 26700 aaggcaactg caggcgtcgg cgtaagcacc ttcctttttc caagcactac aagcagcacg 26760 cctataagtc agtgcaatgc cggcaatgat tgttctctgt tctctggcag caatgaggcc 26820 tatgttgttc actcgatcgc cagacatggt gccgacagta gtgtccatgg cgagcgcgct 26880 gatgagcatc acgactccaa ccagcagcac gagaattccc agggtgcgca tcccttgctc 26940 tccgcagcga ttttggaaag ggacggactc taccatcacc acgccagcac gagaacccag 27000 cacacagctg gactcaagcg gacaaggagc gttctcgata acgcagtacc agacgcatcc 27060 tgccgtaccg ctgggtctac ctcagtcgtt tcaaggctgg atagaatcac agtgccacca 27120 gcaactcagg tcccgtaatc ttgaacagcc tcgtcaaaac agaccacgag gccgcaatgg 27180 atatctgcca cagctacaag gagcatttta tggccgaaaa gtcgtatcta attgggaagt 27240 gggcaatttt caagagcaga gcctcgacgg aggtgcttgg ttacatcgtg gatggcattg 27300 gacaaacgac ggtgcctgga cagccaccct tcagcattat tgactctgtg ctctttgccc 27360 ctgacggcac caggctcggc tatctggctc cattggaagg aagctgggtg gtgaacctgg 27420 gcgactatga gataggacat gtactgcgtg ccctgccgta agacaccgga aggtattcac 27480 ctgacaatgg agatcacatg atcattagaa gtctcgtcca caatctgcct aaagacccgg 27540 gcagtcccgg ctgggttcta ggctgggcgg ttgtccagag cgcaccttgg agattcatgg 27600 atatttatac gtccaaggaa gcagtggacg ctgaggcgtt actgcacggc gaaggcttcg 27660 gcgtcgaata cggctcgcac gaggtgggca ctgacaactt tgtaggcgga ctcacgccgc 27720 cgagctgatc gcttcgaagg tgatacgccc tggaccagaa accagtcgtg cggtgagccc 27780 aggcttcccg gaatagctac gacaataccc agcgctacct ggactcgtca tgccggcgaa 27840 tctcaatcgg tcgatttcat cctgatcgtc gaggattgcc acgaacgcct cgccgccgca 27900 ccgcacgcca acgcgcaccg taaataggtc atggatggtt agcaagtagc gctgctgcat 27960 actctcctcc cgcggcacag ccgcttcatt tcgcgttccg ataccgcagc gccgatcgct 28020 tagcggccgg tttcagtcaa cccagcacaa ctccgatggc tgctatgatg gatgcaatag 28080 ctacgcctgt ggctaggatg agtgcggcgt tggctagccg cttgccaacg attccagcgt 28140 cctttgcgtt cattttctcc caccctgact gcgcatctct caaccgagca gcctgtccca 28200 cggaagattg ctggacaggt agccaacagc aatcacgaag aaaaccaacc aaagcgccca 28260 aaagcgcggc ggcgacagtt tgtcagtcat gattcgcacc tcgcgaatga tcttgctaaa 28320 atccaagtac gttctcctca tgcctatctc atggggtgga aacaaaaacc cccgaagccg 28380 gccagctctc gggggttttg cttttttggc cggtgaagcc aggatcgccg atttagaagg 28440 cgttgttttt cgctttcaag caagaatctg gtctgattta aggtggtcac caccggaaac 28500 gacgaagcct gcactggagc ctgtcagatc tgtacgcatc cccagctacc ggcatcggaa 28560 gaggcgtagt agcgttatga cctcacaggg ttcccgaccc tgagcaaaag ggcccaggga 28620 ccgggtgcgc caaaatcggc gcgagctact gaccacggag gtcaaatgtc catttctgat 28680 agaaacaccg gcacgccctg gagcgcagag gatgtcgccg aactcaagcg cctcgccaaa 28740 gagaacacgc ctacacgtgt tattggcctg aagcttggga gaacggagga cgccgtctat 28800 accaaggcgt ctgagctcgg cattagtctg aagccgacga accagtctcc ctacaaccgg 28860 cagaagtaga ggccagctcg atagcctctt cgtaggcttg gcgctccctg tccgaccact 28920 tgtggccgtg acttgcgagc gctactgcca gcacgtccag gcatgcggtg attttggtgc 28980 aagaatcgtt ggtgttcata catcctcctg cggcctagcc gctttagcga ttgatttagc 29040 tgacgtgccg cagcaccagt cgcatccggt cgagccacgg cccgccgaac acgatgattt 29100 ctgagggttt cccatacagg tggtgcaaca ggaacggccc ggcgccgaag tgctgcgcat 29160 cctcgccagg tagtgatggg tcgtccgcca ggtagatccc agcgtggttc gggtgcgcgg 29220 tgcgccccac cgccatcacg atcatgtcgc cgcgctgcgg ccggtccacc cggatgaagc 29280 cagcagcctc gaaccgctgt tcgtagaggc ttggaccgtc tgcccgctcc caccagccat 29340 cggcacgctc gaagtgcggg aactcgatgc cccactccct ctggtaccag tcggcgcaga 29400 cctgccagca gtcctgcacc ccatgcacga acgcgcgccc gagcagcggc acctgatcga 29460 cgggctcgat ggtacgcagg tcgccctccg gccagctcag gatgtgccaa gtcaggcccg 29520 aggcgttgca catcgcgaca tctgcggcac tcggtcggct ggtggcatcg gggtggctat 29580 gcaccacggc gacgatctct ccctggtcct ctgcctctgc atacgcctcc ggcgcgatgc 29640 ggaactcctc gccggcgtcg gcagcggtgt tttcgcaggg aacgtatcgc tggctccggc 29700 cagaacggat gatcagtccg cagcactcgc gcggatactc tgccgcagcg tgcttctgca 29760 cggcagacag gatgtgcttg agcatggtca gctcctggcg atgatcgaga cggcagggaa 29820 gccgccgaag ggcagttggt tgccttcacc gaagcgcggg atgcaaccgg tgcccaggca 29880 gccatcacac tcgtcccggg ctgggtcatc ggtggggttg ccgtcgatgt cgaagtacgg 29940 gccggtgtag ccgcagtcgg gcccgcggta cccgcccgtc atcgcccagt ggcacagggt 30000 ggtcatctgc cggccgacct gctcgccgcc aacgtcgcct ggcgaggcca gttcccaggc 30060 cacgtactgg ccgtcctcgc tggttttctg gtccaagtac cagatttcga cgatctcctg 30120 ggagggatca gcgtcgggat tgccgcctgg gaagttcgcc gcgtccagat atttcgcaag 30180 cgtcgtccgg atggtgaggc ggaactggag caggtcctcg aacgccaggc agagcgccgt 30240 aatccggcca ttgacgttgc cggcggtgaa gctcggccgc gccgcagtac catcgctgtt 30300 ggcctcgatg ccctcgatct gcaccggcca ggccgcgtat tcgcggccct gccaccagat 30360 cgatttcgcc ggcaactggt cggcgttggc gccggcggcg gccagttcct gcggactgtg 30420 cgggatagcg tgaccgtgga accggaccac gtcggcgccg aagtcgctgc cgtcaagctc 30480 gaacaacacg acctcgccgc ccggctccag cttctggata tcggtgatca gtgtcatgga 30540 tggaatgcct gttcaaaggt cgcggtcagc cggtagaccc ggccaccgag gttgacgggc 30600 cggtagcccg cacaggtgta gaagcccaag tcgcccaggg gcggcgtcca gagaaatgca 30660 cgcgctccgg tgtggcggtc caggaagtcc atcacggcct tgatggtcgc cgccggcccg 30720 gtgatggaca ccggccagct ctgggacttg ctgttcagac cttcgctcac caactgcttg 30780 tagccgtcac cgaattgcgc ggacctggtg gcgaaggtta tgtcgccctc gccaccgctc 30840 tcggtggccc aagtgaaggt ttcgattgcc atgtgctcta cccgttgatg gcccggccga 30900 tcgcaccgtc acgccgcaga tcacgcgcca ggagttgtcg gtatttctgc tcgacgaacg 30960 tcccgatgtc gcgaccgaac tggtccaggc caggctggct gctggagacg ttggccgaac 31020 catccgaggc aatgttcacc tcgacgttga tctgcgaacc gccgccgccc atagcgcgca 31080 caccgagggc gccggacgag gttctggtca gcggcatcac tgcctctggc cccgcttcgc 31140 ccatcacacc caggcggccg ccgctcatgc cgaacgcggt tggcgtgctg accacgctgt 31200 tggtgaaggc cccgccagtg gcgaacatct gcacgccgcc ggcgaacgca ccaccgttgg 31260 cgaacagccc gctgttgctc accaggttgt cgacacccga ctgcgcggca gcgtttccac 31320 cgccgaagaa gccgccgaag agggacgaaa gggcctgcga ggcagcggcg cgcgttgcaa 31380 tccgcgccat gtccgccagg atgctcttgg cgaagtcgga gaacgacagc ttgccggtcg 31440 tggcgaagtt ggcgattgag tcctccgcgc tgctgaacgc gttggtgagc aggctcttgg 31500 tttggcccgc cacgtcccga gcactttcca gataggtctt gaacgccgat ctggctccca 31560 gcgaccaatc cttctgagcc tcatcgactt gatggaagta gtcgttctgc ttggccagcg 31620 ccttacggtg ataatcgtcc agagcagaga gttccttttc gtactggctc tggctgatac 31680 cgccgttggt ttcgccgcgg ttgcgctgct cctgcagttt ggcgctctgg ctctggtact 31740 cctgctccag cttcaaacgg tcctgaatgc gccggcgctc ttcatcgccc gcaccaaggc 31800 cagcgatctg cagttcgtac ccctgctgca ctgagcgcag gcgcccctca aggtttgcgc 31860 ggtacgcgtc gatcctggcg atttcctcct tcttcctcgc ctcggcctcg agcgccacgt 31920 tcttctgaag ctgcgcgcga acctccgcct ccctagccaa gagagacttt tgatcggcag 31980 tcaggacagc tttcaccttc aggtccgcaa tctgctgctc ccacttcgcc atctcacgct 32040 gcgaagcgga cagtttctcg ctggtaccaa gttgctgctc cagggctccc tgctgctcgc 32100 gcagacgcaa caggtactgg gtagcagcat catcacgaaa ttgagaagac ctggccgcct 32160 tcgggtcctt gaaccgctga ttgatgccag ccaccagctt gtcgaaggtt ccgcctgata 32220 cgctatcacc gacaatattc acacccttga gccagtcggg aagcgcgctc aacttgcctg 32280 ccgagatcat cttctcggcc gcgcggtagc cggcgacgta cctcttggtc agctcatcaa 32340 tggctttcgc tcgcttggcc gccggggaga cgttgcctaa ctggtcgccc agctctttct 32400 caatggcgat gagctgctgg tcagcctcgc ccagctcagc ctccgacttg gcattctgct 32460 cggacaagtc ttttcggacg agcaagaggc tgttctgctc cttcaatgcc tctgtggagc 32520 tgaactgatc ccgaaaggac tgaaatagtg ctccggtagc ggccacgcca ggcaagccag 32580 ttgcggcgcc agttagtgcg ccacgcaaag cattcgacag aaacggagcg ttttgccgtt 32640 gatccaatgt ccgttggagc gtctgtattt gctcattgag ggttggaaac aagtcagcac 32700 ggattgcagc gtaggcatta ccgatcgccg ttttaactgc gtcccatccc tgctcaacac 32760 cagacagaga ctcgcgatac tgtttcagcc tctcctgagc gttacgatgc agatcctcgt 32820 tcagttgatc gacagcctgc tgatggtcgc cttgctcatc gatcgccttg atcgcctgat 32880 attgctcgta actcagcagc cgatactgct cgctaactcg tgccgctgcc ctagtcgcat 32940 catcccccag ctctgacaag gacttcgcca catcctcaat atcccgcccg gtaaattgag 33000 cgattgcgct agtcgtttcc gtgaggctct ggagttggcc ggccccaacc tttccgctgg 33060 ctgccaatgc aatagcagct cgattcgcgc tggccaatga tccggagacc gaagcagcct 33120 gcttagcaac ttgggccaga gccgacccag tcatgcctgc cgcgccattc ccagcaaaga 33180 tagctttgct gaaggaggca gcctttttct ctgcgtcgta gaaagcaaag ccaagcgtgc 33240 cggcagcagc agccaatccg gtaattgggt taatcaagct cagcgcatac ccaccaaccg 33300 cccgcagagc cgggccaatc ccgccaaacg agtctttgat ttgaccgcct tgctgcaaaa 33360 atacctgcat tggcgactga ccagcctgga ggctggtgaa tatgtccgta aactgcgcgg 33420 gaagcccccg catagcggcc tgggtttgcc tggcggtaag gccggtccga cccaactgat 33480 cgttgaacct ggcaaggttc cggctgccgg catcgagacc ggtagattgc tcctgaactg 33540 cggtagcgga cttcttggcc tgttcggcaa tgcgctgctg agactggatg atggcttgcc 33600 cgcgagcgtt gatctcctcc tggtacttgg tccagtcgat ggtcgaggca ttcgccttct 33660 cgagggctgc gctactgctg gtagccgcct tcgcaagcct ctgatggtaa tcactagcct 33720 ctagcgaggc gcgaaccata ttggagatac gtgcggatgc ttgggcagag gtttctccga 33780 ctgaatcaac cgcgctttcc gcactgacgg cggaaccagc caagcgatcc agatcctgag 33840 ccgcctggtc aacgccttgc gagttcaccc gtacgccaag ctcagctatg gtcgtcatgc 33900 ttttctccgg acaataaaaa accgcccggg ggcggttctt cgaacaaact cttagctgag 33960 tctaccgacc tttgagccag taaagatcac catggatatg gtgcgaaatc ccaagcgctc 34020 tcaatactga gttggccgag cgcttgtctg ggaatggccc gactataacc gtcaagcccg 34080 agactgaagc tacaggcagt ttcaactcat caaacttggc catagcacta tcaatatctt 34140 ccgcagactt acacttcact tttacagccc agcctacact cagtccgact ggggctggct 34200 tctccggcac cgcgtcaata tcagccccac agtaacgaca ctttatcgca gcgcacttaa 34260 tcatctctgc acagtacgga catggacgaa gctcatttgc ctgggtttgc atattgggat 34320 tgtttccgct cactgcgccc ccgcgctcac tctctcctgt agaggatgct gcccacacca 34380 aggcggcaac ccacccaaca aaggtccacc cgagaaacag attcagtaca atgatcgccc 34440 ctttattatg atgtcttcta ttctcagcga ttattgcagg tagaaagtag aggattaatc 34500 cacccatcaa aaagataaaa ccgagcagca aagaggaacc gttttccata tccagcctcc 34560 taaaagcccg caatctacca tcaccacgcc agcacgagaa cccaaccgtg tgcggatcta 34620 cgtggctgaa gggggctctc ggagccgaag catcaggcag tctattcctg agctacctgg 34680 tctgaggtgt ccgagtattc ggcgatgcca agggatgcaa tatccatcac acttatcctt 34740 catgaattgt tgacagcgcg gcggcttcca tcatctggat ggcatcgaac agttcggacc 34800 attgcgcctg cggcactccg cgcagccgta agatgtcctg taagacgccg tagtccagtc 34860 cagtgggacc gttcatgcct gttcgccact gggtggacat gtcgcgaaac aacaggaaag 34920 cccgccagtt ctcaggccag atggtcacct cttccaccgg taggtcatca ggcctgagcc 34980 ccagcgcagc aagggcctcc gcatcaggcc ctgttttgta cagggctgcc gccgcgctgg 35040 tcagtttccc aggcgggcct gggtgatctg ctccatgtac accctgacaa ctgtcgggcc 35100 ggcgccgagg tagttctgca gcagccgctg gacgttctcg tcgttgaacg cgtcgtcgag 35160 ctcccatcct gccgcgacgg acataatcgc ctcgcggtca gacagttcgc ccactccctt 35220 caggaatgcg tcgagatcat cctttggcat gtgcttgaag gtgaacttca cctcggcact 35280 gccaccgcca tgcaatggga ttggtactgg agcaatgaaa gtaggcttcg ggtccaggga 35340 aaacttgact ttgctcatac cccctcctta cgccgccagg tatcgaagcg gacgaccaga 35400 caggccaatg ctgatggtgc gggtcatcaa ctgattgcgc tccatggtcg gcgaactggt 35460 gatgctcacg tagccgggat acaggatttg gtcaccactc ggcagtttca gccggatgac 35520 ggtcagtgct ttcgtttccc caagactctc gaccacatcg acatatgcgg cggacggctg 35580 gtcttcgacc gtaatctcca gggaaagcgg gttccggttg gtggggaact gccgatcatc 35640 atcctcttcc aggtagccga cggtcaggta ttgctgctcg ccccccgaag aggaaaagcc 35700 ggtgaccttc gagatctgga cccaggtctc caccggagtc accgagccaa cgccggagtc 35760 cggggtgtag atctcggtgt tggtggtatc cagtccgccc aacgcgaagg tgtcggatgt 35820 gacctctccg atgcggctgg cacggtcaga gattttggcc cagccagagg tgatcaatac 35880 ggcatcgccg acctccaggg agtgaccagt agcactggca atcggcggct ttgcgttggt 35940 aattgccgtg aaagcaacgg cggcccccag tgtggatgca atttccagca cgctgccatt 36000 tggcagcggg aagcgtgcgg ccatgagtat ttcctcttga aagcccgcca ggcggcggat 36060 ggttgtgccc gatcgggcta ttggtcagcc gcgccgcgat aggcgaagct ggttgggacg 36120 atgtaggtgg cgtcatcgaa gatggtcggg ccctgttcta cagggccgga aacaatgcct 36180 tcgaactcgc cgcgcgacag gcgcgagtca acgcgaaaca gagaagtgat ctcatcaaca 36240 agcgattctg caatccctaa tgactggccc gacgggcaga cgatgctgac ctggtagaca 36300 ccccgaaact cgagagcctc gccacccaaa tgaggggtgc tggtcccgct tggaagtaga 36360 taccctcgga ggtatgtctc tccagcatca ggtgtaaaac tggatgcttg aaacgccacg 36420 cggatgggtc ggcctttcgc ccatgagttg agcttttcct cgatagcttg gcgagcaaga 36480 gaatgggaca tacacctctc caaaaacgac gaagcccgct caaggcgggc tttcgttcgt 36540 cggggttggg ttaggcggct tgcggataga tcaggcggag ctggcccggc agcccgaatg 36600 cctgcatgca cctagcttcg aagtctttgc ggtcaatcga actatccgcg atcagcgtga 36660 ccatgcggat ttgctggtcg agccgatcac ggcctccatc ggtcagccac tggtgcatcc 36720 tttcgctttc accgcggcga gcctttagct cggcatgcac ctccttcggc aggatggcgg 36780 cgtaaatcca gcggtcggtg atctggccat agatagccgg cgttcccttg gcatgacctt 36840 cgaaaacggt gccggtgatc ctggccagag cacggtagta gtcatcgccg aagcgcttct 36900 cccatggagc aggagccgtc agcaggatca tacccatcac gctgtccagg ccggcttgat 36960 tacgggcgtc gcggaaagcc ttcaccagcc ggagcttgag gtcgaccacc aggtcgctat 37020 tccgggaaag gctcaggaga aagtacgcct gatcttcatt cagcaatgcg aaacgctcag 37080 ccctgccgcc gccttgggcc cgccgaccaa cttccttttg aaacggcagt tggccaagtt 37140 cctcaaactt ccgctgatag cgcgtgacaa gggcaaagct gtgcttgtgc ttaaccccta 37200 gttgctcggc aatcacgcga ctatcgacgc gcgcctcgcc ggcggagtga acaagctgaa 37260 taacatcggt catggatata gctccttccg cctggaatag gtaagcaggc aggggcgtag 37320 gcggagcgga ccgacccttt tcggtagcga acctagcctg cttatttgat tggtctggtg 37380 gccgagtaga gacgcagcgg ggcggacgga tgagcggaca tccgccgttc ggctgtacgg 37440 gcctagctgc gtgttgagcg cccttgcggg gcggattgaa cagggttcag ctacacgcgg 37500 cccgccctga cggcggcctc cacaatctgc tggaattcgg cgatggtcac ccggaccatg 37560 ccagccggct cctggctgga gtgcccgtac tccagcggta ccgcatacgg caggttgttc 37620 accaggtagg cggtatctcc gagcttcagc ggctggaccc cagcggtcac tgcagaaatt 37680 gccttgctgc cagtcgggtc gacgtcatca atctccccct gtgcggccgt gccaatgctg 37740 aactgccagt tggcccgaaa gcgcccgcca acatacccgc gtccggccac catcccgttg 37800 acgtcgaagt tctggtcacg ctccgccttg gtcagcggct ttgcgtgctt cacgcctcga 37860 cgcagattcc cgttcctggt gaagttgctc ggattcaggt tgatcagggt gttgcgaatc 37920 gcgacgttct cgtcgtagcg gtccgccgca gcactcgctc gctggcggta ggcgacgttc 37980 gcggcccacc gctccgggtc accgactgga gatttctcga tcaccttgac cgacaggtcc 38040 agcatgatcc gctggtagat cgcatcgccg gcagccaagg cttggtcgcg gaactcagca 38100 actgccgcag aaaaacttcc ttgccggcca gaataccgct gccgcatatg cgagcctctg 38160 gccacagcta tttcctcatc tggatggtcc aggtaacgct ggcagggtct tccgagacat 38220 tcagagtgcg gtagtcattg atgaggtccc caaccatggg cgtctcggaa agctctgcct 38280 gtagaacgag cagtttggta tcgaaggtct taatcagaga tccatcaatt tcgctcgcct 38340 tgtatctgcc aaatacaccg cgaccggaat aggtaatggt cgtctcagaa ggcccaccgg 38400 tttcaggatc gtactcaccc tgaaccttgc ggacgccagt gaaaggctta actgcgtcgg 38460 caaggtcggt gtcgaacgcg gcagcaatgt ccgcatgaat ctcgtctcga aggcccatga 38520 cctaccctct ggatagcttg aactggctca tacctccgcc agaacccgac agccaggggg 38580 ccaggagcgc catggctagc gactctccgg cggtgaatgt ctgagccccc tctcggtaag 38640 tcttgctgct cgataccgtg tcggcactga cgctctttgt ttggacgcca gtctctcggc 38700 ttccatacac cagccctttg gctgcatctc gcgccacctc tgctccagca agcttccact 38760 cttccggaat ggagttcagc tcagggagct ttcgattggt gagccagacg ttggcgatca 38820 acaccgcgcg ctccttcttt tcaggagagg cccaatcgga gcctagagca gcatcaacgt 38880 ctgcaacgtc gatgtaggtc ttcattcgga agcctcccgc aacgcttttc tcaccctctc 38940 aggcccggcg ttacggtgga cgctgacacc ccgcgccttg gccagtgcgt gcagttgttc 39000 ggcgtccatg ccgtccaagt cgtcgtcaat ggcgggctgt tcctgccccc ttgctgcatc 39060 gctagccagc ggagcaaaag cagcatcaac gattcgatac cccatcgccc gcaactcagc 39120 cttgcgctcc ggcgtgatgg gatgcggttc gtatacgatc gtcatttcga ttactccgga 39180 gtgaagacag cagtcaccac gttcgccgca acacttaagg tcaccgttcc gcccgcgact 39240 gagattgttt gaccgttggc taccacagcc gcagtcgctg ccaaacggat accagcgaga 39300 gccccgcttg caacatcagc ggtaccggaa gctagcgcca tcgagccgct ggcaggcagc 39360 actgaaacag tcgcgtcatt gctaaccaca acctggcctt cacccactgc cggggctgga 39420 ggattgtccg ggtcgaacac cggaaggcct gcatatgcct gaggaattgc acctgctgcg 39480 tagtcgccag gaaccacata gtcaggctca accgccccat tgtggacagt tacgctatag 39540 gttggcgggg tgagagcgtt gagttgctca actacggact tctctgcctc ggtcagcgca 39600 ggtcctgccg tgaaaaacaa aatccgctga gtcatctgga cctcctattg cgcggacggc 39660 ttttacaccg tccgcgccga tggttaggcc tggccgacag ccagaacgcc agcggtatgc 39720 ttcacactgg ttgcaacctt gtcccagttg gctccggtgg acagagcggc atcatccggg 39780 gatgccccac cattagctac atcccaggca tacccgcgca gccctacgcc gaagctgtag 39840 tcgatctgca gagtggtctc gatgcgctct ttgccgttgc tggtctcgat gttcgagatc 39900 aggtctcggg catcgtggac agttgcggcg ccttgggtca gcgagagtac gcgacgcttg 39960 gcaggagcag ccggatcggt cactgctggg gtgtagagcg ccggggcatc ggtcaccacg 40020 atcaagcgac cgaggatatc caccacgcgc acgccgttgg attggaacag ttgctgagcg 40080 ttggtcagat tctggccaat gaaggtgtgg aactgggcac catccataac ttgcgcgatg 40140 agctggctag agtggtcgcc gaacagcgcg tggctatcgt tgaccgcaat gtagtccact 40200 ttcttggcat cggacacgtc gacagtggta gcggcgcctt ggttgctgat ggcggctacc 40260 agggcggcaa cggctgtgtt caactgatcc tgcagaagag actcggcgaa gtagcgggag 40320 gcgacttcga caccttcagc agtcggcttg cgcagccagg tcatttggga tggttcgtat 40380 cgaaccgggc cgaagccacc agccaccttg acggtattgt gcttcagctg ggtcagatca 40440 accggagtta ctgcgtcatt cgagccgtag cggttcacgc gacggcgagc ccctgccagg 40500 cctgcataga aactggtttg caggaagtcg ccgtcgaagc cgtcagtggt cagaaggatc 40560 gcgccaccgg acgccgcatt gaatcgctca accatctggc tcagcgtctc gacggtggcc 40620 ggcatgaaat aggtgttgaa cacctccata tcggaaagtg ccatggtgtt tcctctctag 40680 gtgcgcccgg atgggctgga tttagtgaag tgtcagggcg tccgccctgg agcgccgtac 40740 cccatccggg atgacagcta gactccgatc aggccttggc cagatcaggg aattgcgact 40800 tgatagcggc gagccggtct tcgcgattgc ctccgaagtt gcctttcagc ccaccgccgt 40860 ttgccggcgt gccgccgtta ggggcgccgc ttccagactg gttggctcct ttcagaatct 40920 ggtctttgta ggggtactga tcgaccaagg tttcgagcgc ttcgtcaaag tcagccacct 40980 ctcccgggcg ggatcggctg aaaatcttgt ttcccgcctg gtcgtaggcc actaccttgc 41040 cttcttcgat ccggaaggcc tgaccgaatc gggcctgcac cagatcgccc gggatagcga 41100 atttgtcggc gatgaactta gagcggctaa agctgccacc aatcaactcg ttgtgcagtt 41160 gcccctggag cttctccaga tcaccctgaa gctgcttctc tcgctcagca gaggctttcg 41220 ctgcggcctg aacctgctct tcggcagcgc gcttggcggc cgacttgatc tcttcgactt 41280 tgccagccgt aacgagatcg ccgtccttga ggttcttcac tgtttccagc gccctgactg 41340 cagcttccgg atcgtcgatg ccttcgaaca gcttggcgcg ggcctcagcc gcctcttttg 41400 cctcacgatg gccttgagcc tcacgattca gggccgaaat ctttgccacc gccgctgcgg 41460 catcaaacgg agcctccttg ccatcttcgt gcacgtagat gggcttcccg tcttgcagaa 41520 ctgcatttcc gttttcgtcg agcttgagtt tcatggtttc tcctgggcat ccgcccggtt 41580 tctacggcca tccggccacg cgccctgttc atccgaacgt cgggcatgaa aaagcccgcg 41640 caatggcggg cttggtgttg aagtcttcgt tcagtcgggc gcatagagtg ccttgagttg 41700 ggctaggctc agcgggttgc cccgctggtc caacaggtca ctcaaggtga tgacgcctcg 41760 gcgccagagg tcggcgcggc cgggccccag cttctcgtcc tggaaggcct tcgacttacc 41820 cttgagccat gtctcgaagt tcagactggc cggcacctgg ccgtccatcg acgcccgggt 41880 gctcttcacc tcgtcgacgt cgatacctag ctcacgcatc gttttgagcc aaggcagagt 41940 ggtactgcga cacccccagt gccgcgggca accttgcttg tacggcaacg agtgccccac 42000 aggcatgaac tgcagatccc aggtcttctg gtcgtagacc atgcagattt cagtggtgtg 42060 cgagtccagg gtgctgagct ggcgatagcc tttcaccggt ccattttcgc cagaattggc 42120 cttgtagacc tccatcctgg cgccattggc caccgcttgg gcgctgttgt ggaccaaggt 42180 ccgagccgcg cgcttgctga catccatgaa gcccttcacc ggcggttggt cgccccgagc 42240 ccggcggcca acgatctggg tgaccatctg ttccgtggtc tcgccgttca cgaagccatt 42300 gcgcaccaca ccggcgaacc gaaacgacac atccgcagcc tgcttgagcc accattgctt 42360 ggtaggcgcg ccctcgatga gcgtattcgc aaccacggcg ctgagtcggt tcttgccgac 42420 gccgagcatg attggccggc tcaccaggct gttgactgag ctcgacgcga agcctccttc 42480 gatgaccgcg agttgccgaa gattggcatc atgcgccgca gcgatctcgg tgtactgcgc 42540 cttgattgcc ttggccgcct cgtcgaggat cgcgttgacc tccttgacgt tcttcaacgg 42600 cagccgacgg ccctgtagga gcttgataag ctcctctgcc aactcggtga tcttctcctc 42660 aacttccttc gacatacccg ccgtggtcct gatcaagtcg ataccatggt cggtatacag 42720 ctccgccagc aagatttcca agcgagtcat atcgtgggag cctggttaag aatgcgctct 42780 tgctcgtcct cccacttcaa cgagtcgctg atgacgccgc ggcgcttcac ctcgttgaag 42840 agagtttcct gacttaggaa gttggagtct gccatctgct tgagcactgg caggctcacc 42900 tcgggcgcgt agtcggtgtc gtagttgccc tcaaccgtcg caaagccacc gctctcttga 42960 ttcgtccagt ctgcgaagag ttgcagcatt tggtctattg cgtcctcaaa cgcattaccc 43020 atggtttcga gggcgctaat cttctccgca gcctcttcgt tggcttgtgc agcggttttt 43080 accgcctggg catcgcgatg aaggagccta gcgccggcaa tgcgcatctc ctccagcagg 43140 tcctgcaagt cctgcctgcc ggcctccata gccctgccgc catgctcaac gaacttaagg 43200 tcggcaccgt caccgttaat acgcgttgcc gaggatgttc ctaccgtcat ttcccatgga 43260 atcggcgatc cgtctggccc gaccgcatcc ccagcattaa tcgccaccag aataggtact 43320 ctcgccacgt gcaggagatt gcgctggtcg ctttggctct gccaatgagt aacattcaga 43380 tgtgccagct caatcagagg aggcctggcg gtcatgatcc cggtctggcc ggtgtagaac 43440 gtcacaagcg ggattttgtt gagagtggtt ttgccttcat catgcaacgc ccaaccactg 43500 ccatcgcgtc gataggtagc ccagcggttg atctcaagaa cgcgaacctg ttggacattc 43560 ttggatccga actccccatc ttcttcctca atctcctcca tgtaccgaaa ttgggtaagg 43620 acagggcggc cgcgctcgac tcgataccga tagcccagaa cttgctgcgg tcggattaga 43680 acggcataag gacgaatccc ctcttcccgc tcctgggcga tagttttcac gccatccgac 43740 ggcgggtagt caactaggca gtggcacagt ccgtagccaa gcccagccct aaaccactct 43800 ccggcaaaca catccaggtt attccccatg aggtcgatgt cgtcattaca ccaaccagcg 43860 atatcaccgg ggacttcatc tcccagtgtg atcgggcgcg ccagaacgcg accggccagg 43920 ttcttgactg tctcagagaa cgctggaagc agagtcgagc gctgcagtct ctcctggtag 43980 ctttcctttt cctcttttgg ccacttcggc aggtgcttct ctcctgcctt tcgcatcgca 44040 ttagtaccgc ccaggaggtc tgaaaccagc tcccagtctc ggcgcatcct ctcaacggca 44100 tcgagaacga tgtcagggct gtcgttgcta gacatggggt tacatcctga gtggtgtcga 44160 ttggactggg cgagcgttta tcggataccg cttggcgatg aagtagccgg cggcgtcgtt 44220 catgtggtcg taaccattct tcgggttctt gtctggctcg cccttgtcgt tgtaggtctg 44280 ccgttccagg cacagggtca gttgcggaca ctggtcgatg ttgaccttga gtcggcgctc 44340 gccgtatgtg ttcagcagca tggcgttgac cgagttcacc cggtctttga cgctcgggtt 44400 ctgggtgtcc acgatcaccg tgaatccagc tttgcgcagc agggacaggt ccgactcgct 44460 cgcgttcttg ctactggtgt tctggccgct ggcatcggga tagacagcta tgccgtggcc 44520 cgggaatcgc gccttgattc tctctatcat ctcaggcgta tcgcgcaccg agtgaaactc 44580 atccagggcc aggggcaagc cattgcgcac gacgtagacc accgcagcca tcttcatgac 44640 gttgaagtcc atgccgatgt gcagagcctc tcccggcttg attcgctcgc ttgtgctgtt 44700 ctcgctacgg ctaaaggtgt agtagacaac cccggagtag ttctcgaagc tggcttcata 44760 ctcctggcgg aacgtgcgcg gatccatctt cctgcgggcc gcttccaact cctcagccgg 44820 gacgttgcca ccctgcagcg atgtatagag ccagctcttg tggtctggct cgccgccgac 44880 ctgaccgtcg cggtaggtgt cgaagcagtg gttgaagcct tttggggtgc caattcgcag 44940 cgcgtggccg cccttgcact tgccgatacc tggcacgacg tactcgcacg tagacagcat 45000 cgggcgcagc acttcttccc aggccgccca tttgcagtcg gcccattcat ccacaagaac 45060 gaagaacagg ccagagccgc gcaggtcgtc gtagttctcc aggcccacac agcgaatcag 45120 gtgaccactc ttgagcgtga tcagcatgtc cgactcgttc ggcttgcact cccgccactc 45180 tcgcgggatg gcttgcttta gccggcgcca gaacactcga cgagcctgct tctgcgtcgg 45240 agccgcgtac cagatctcgt cctcgatgct cacgccccac tcagcagcca acctggccgc 45300 gcggcgcatc tctgccttgc cgaggaacgt cttgccaaac cgccgaccac agaccgcatc 45360 cctgaagcgg gcattacgct ggaagcccca gacgtagatg tttgcctgct tcggcgtcag 45420 ttgaacgggc gcatcatagg tacggggcag ccgggacatc ttcgtcaggt ctcaggatgt 45480 actcagtttt cgcctgctgg tggtccggct gggtactcag ggatcggtca ggctcagcct 45540 ttcggttcac atagacgtca ccgcactcct tggccgcctg ttccaacaac tgggcggtca 45600 gcgctaggtt cctcatggac tcggcctttt cggccatccg ccccagcgtt cgaagccgga 45660 acgcccggtt ggcgataggg atctcggacg tctcttcgcg aaagcgcttg cgggtgtcct 45720 cgaacagagt ccgccagcgc ttggccaggt ctcggcctgc gctcttggtc ggatcatgcg 45780 actcgcactg ttggcggctc acctctatac cgaattcttc tcggacagat gccgccacct 45840 gtgcgggggt atcgaaacag gccagggcct gcacgatgaa ggctttcacc tcattgttca 45900 ggactgccat atgggctcac tccgtcttag ctctgtcatg gatcaggccg acttgagcag 45960 acaggttccg caggccctcg cgatgttgat ctttgccact tctggcggct tgctggcagc 46020 gtcgatcatc tcttgcactg cctcactggc gccgtagcgg cgcaccaccc cgacgaactc 46080 attcacgtca tgcccgcgca agtagaggct cggcatcccg tccgagctga attttggcgc 46140 gccgaactcg tctgtcttct gggctatgtg aaatagttca tgctccaaaa gcgagcaaaa 46200 ctccacgtcc gaacactgcg agcagtagtc agccgccagg gtgatgagga agtccggctc 46260 ttcaccaaac cattcacgca tctgctgctc ttgccgggcc ttctgccaac ctccagcgcg 46320 gaacatgacc tgctcggcct ggcccaggac ataacggcct tgcttggtga atccagagga 46380 tgcccagagg acgcggatgt tcgcgtcgat caggtgggca tgctcagggt tatggatgct 46440 gccggtgtca gcaaggatct cgcgctgaac ccaatcccac acgccgatag ctgggcgcag 46500 gataagccac agtgattcga gcatctcggc cggcggcatt ggtctactca tggatcgcct 46560 gtatcttgaa atagcggcgg cttaccgcta ctgatggatt tccaatcaat gcgaggaaac 46620 gcaatgtcga aagctattga cgcaatactg gagagctacc aacggagcat cagcgatggc 46680 gagaagcgtg ccattgccgt tgccgcagca ctgcaaatta ttgaggccaa ggtcagcaat 46740 gcacccacca acaatgcagt ggttgagaat gagttcaaca acttgaacaa atatgccgat 46800 cagatcctgg ccgccctcaa gggcgaatga gccaacagtg ccgcacttag ctgcggcaca 46860 cccaaacccc gacgtggagc caacatggac attgatcatc aggaagcccg ggcgattgct 46920 gacgagcttc ggcgctggca cgacgaagct cgcagcttga ttgacgacgc cgctgataaa 46980 tccaggcttt cgcctactgg tatcgactca ctcaaaaccc ggctctctat tctcaagaac 47040 gagatcaagg aagcggcaaa gcacgagacc ctctcaaggc gaaaaaccgc aaagactgaa 47100 ctggagcagt gcttcttcgg tccggcagtc agaagcacat cggccaattt ccgcttgcgc 47160 actgacacaa gccccaaaag cgagctttgg gcgcgtggtc tgcatgaggt ggagtttgag 47220 ctctcttact ctatcgacgg cctagagcgt ttcgtagctg aaaactcgta gcgcttcgcg 47280 ccacaaaacg gtgcatttcg aatttgtggc gcgttacccc ggctggaaca catgatcgcg 47340 ccggacgacc ggatatcgga gccatcacga tttcccagtt aacacgtaac gacggattgc 47400 ttgaaatcct gggcgatgcc gatgggtggg cactgataag cggggtattt cggagttcgc 47460 ttctcgaaga cgagcttcag atgatccttg atctgcaacc actgcatttc gtttggcaga 47520 gccccgttta attcgacgaa accttgcagc cagtatgtga attgttctgg ggtcatcagc 47580 tgcgccttcc cttaattgcc tcaagatacg catcgtatga gatgcgcgac tccatctctt 47640 cgccgcagag cctcacccgc ttgttaacga gtgcgaacgt gaccgtgacg gttggaacag 47700 ggccgtcgtt gctgaccgtc agcgaaagct ggccagggag cggcttcccg ttgctgtcac 47760 acaaaatcag gaatgtgccg gtgttcttca gtagaagcgg agcatccatc agtacaccct 47820 cagaatgtgg gccaggttcc cccgcgcacg acagacaagg ccgagcagga tcgccagtac 47880 cagggtcagc caaggggaga caggattcag cctgtagccg tgtagcgcat cgagcatcac 47940 gctcagggcg aaacacccac taccaacgca cagcaggtag gcgagccagg aaacgccccg 48000 gcgatacctc gcaccttgcc ggcggtatgt cgccaaccgc atgcagatgg cgccgcaaat 48060 catcgcggct accagagtcc aagggtcaac cattacgacc tccaaagcgg tccgctatga 48120 agcggagcca accaggcgtc ttccccccct gcacccactc cagcaagctg gtgcccactg 48180 cgacgcagaa caatgcccca ccaaaggcga ccaggcccga tgtccttgcc cactcccgcc 48240 caatgacttc gccggcgacg tagtagccaa cgatccagga cgcagcgaag taaccaaggc 48300 gagcccaggc cgagatgtcc ttggcataca ccacgaagaa gatagcccca gcaaaagccc 48360 cgatcactgc attggcatca atgccaggga tcaacgcaga cgcaccaata ccgaccaagc 48420 cggcgactgc taccgcacca ctcggctcgg ccatattcac gtactccaga tgcagaaaag 48480 cccaggtcgt tgcctgggcc ttgtagtgtg gctctcacga agaaaagacc cgctcatggg 48540 cgggtatggc cccgtgctat cctcgtgatt cctacaccac gaaacaggac ggacccatgg 48600 caaacttcat tgtcacgttt caaatcaagg ctgatgacac ctaccagtct cggtatagtt 48660 ccttcaagaa gaagatcaat gagttaacca gctacaaaca ctgggatgaa acgacttctt 48720 tctactgctt cgaactggac tacacggcgc aaaggctttg ctctgagctg tacaccggca 48780 gcgagttcaa cgcaaccaaa gacataatgg tggtcatcga tgtatccaat cgagaaaagg 48840 ccacgaaagg tccgatccag tatgctgcac tgctcgacgc ctacctcggc ttctagttag 48900 gtccgcccag caccgaggat ctgcgactcg atctcagcta cacgatgctc atattgggaa 48960 agtgtctctc ggttaagtcg cagatcttca gccagcctac gttcttgggc agccgccaaa 49020 gcatacaacc cttcaacctc cgccagcttt gcttcttgag caatgacaga ctccacagct 49080 tgccggtatt cgcttttcat gtacgttctc cgcgcgcagg gttaagcctc tcagcacttg 49140 agtatgaggg cctggcgtcg agtgggatgg attgagtttg gagcggctcg cgggacttga 49200 acccgcaaca tccgacttgg aaggacagcg ctctgccagt tgagctagag ccgcagaata 49260 ggtgccggac tagccggcgt cacgcccgca gagcaaggag ccggggcttt cgccttgatc 49320 accagtggtg aaccttgctt tcttctgccg catgcgtgat ttggagtggc cggtgctgat 49380 ctccggcttc tggctctctg tgttcgttgc tgcgcctagg cgtctgtgtc accacgggct 49440 tgccataaac cctcgattcg cagcatcagc accgctgcat tcactccgtg ccggtcttcc 49500 accggctccc acttcacttt aacgcctgcg tgtccaaggc gatcccggag tattaggtcg 49560 cggtagggcc gggcacccac ctttgaccat cctcggccgc gtagtcgcaa cccagaagga 49620 ttcagatcag aactactacc gctccaacca ggagcagcag gaccagcgcg ccaccgccga 49680 tacccttgag cagccaaaca tctttcgatt cagcagacat tgcagaactc cgtagacggc 49740 tggaaacgaa aaagccccgg cagatgccag ggcttcggtg gtgactttcg ccagaggcga 49800 atttgtcacg atggagataa gtgtgcctca gccgcacatt tgtcgtcaag cagcattttt 49860 catcattttt atcgccgaag agacaggcac aagcgcggcc ttgtcgagat cgttgcaggc 49920 atcgaaacag gcctggataa agccgtccca ttccctatcc cagtttcttg ggtcaagttc 49980 aatgccatgc atacggtcaa gccaggcgcg gaacgactca gggcttgggc agggatcaac 50040 gccttcgctc tggccgccct ggtgcatgcg acggtaccgg aacaagactc ccgcagcgac 50100 atagcgcgcc ttctcgaatt tcttcgtgta catccttggg ccggtttcgt aagcgaccct 50160 gaacacgatc tcttccgcag cctccttgtc gtcttcgcca gccatagggc tgtacatgtg 50220 attgccgaac accttcagat gcgccgggag ggtatcgatc gccttttgaa tcacgccggc 50280 gagtgcctga tgaacagccc gaggagtgct gatgtcgcgc tcagtcttgg tctggtggat 50340 tcctggcaca aaggtgtatt ggctgtagga gacagcctcc ccttcatcgt cgatctcggt 50400 gatgcgtcga cggacatatc cgccagcctc gacaattcca agagcagctc gctccgccgc 50460 ctcggccatg ccgctgttcc aaggggtata gaacgcatcg tgccaggcaa tgcgcgcgct 50520 gtttagattc atgccgtagc cctcttcagc tcgcgcagct tggcgcggta ctcggcggtg 50580 atcgccttca gttcgtcgtt ggtgtacttg cggggacggt gatcggcttc cagagcctct 50640 acagcttcca ggccgatgcg ttcgatcaag ccctcacgga agccctggga aacggtaagc 50700 cccttcctgg cgtacttgct ggagccggcg ttacaggcct tgcattgaag ccatatgttg 50760 gatggctcca ggcggtgctc gggccttgcc cccttgccga gaaaatgccc tgcgtcgaat 50820 gcacctccag tcttccagcc ttgttcggct agtacctcgg cctgagactt gccgcagctt 50880 atgcagccgc ttccgatgga cagttcgtag gtgcgccggt agtcccgaac ggctttctct 50940 gcatctttga tgtggtcgct gtgcgtcttc agcctctcct tccgaacctt gatctcccgc 51000 cgctcgcggt ctgcgattgc cttccgcgcc ggctttgagt gcttgtcctt gatggccagg 51060 gcgcaggctg gcgagcagac cttttgcgtg ctgctgaagc gaggggtgaa ctcctggctg 51120 catgcagggt tctggcattt cttcggtttg ggctggctgg cggataggct cattgaggct 51180 cccccgaaac caaggctttc cagcagtcgg tgaaagcttt gctgaagtcg ccgtagagcc 51240 tggacgattc ctgccggcag gcccgaaccc cttcgccgac tgcctcgcat acagccacca 51300 caagcggcac ccagccaaag gcgatcatga tcaccaggac aatgagcgct cttggccgaa 51360 caggaactct ccgcatggcg cggaagaaca agctgcggct catagctctt ctcccgcgaa 51420 gtagccaagc catagggtgg ccgtcccaac cattgagaca atccatgggc tgatgggcgc 51480 agaggtctgc gtgtagatga tgagtgcgat gaccagaagc tggcccacca gaatttttgc 51540 aatctgtcgc ctgctcatgc ctccacctcc ttcgccttct gctgctcggg ctggaagtcg 51600 ccgcggaggg gcatgagata ccgttcaggg atgtagagcc gatcaccttc atggagcacc 51660 caccaggctg cccgattcac cagaaaggtc tggccgtctt cgacaaatag atcacccggg 51720 gaaagtcgag atatcaactc gactaccact ccagcgctga tgcagtttgg gatttcttgc 51780 agatttagag cgaggtcgcc cgccttgaac ttgctcatgc ggcctcctgt atcatcagcg 51840 gccacccttg ctcagcggcc catgcttcga tcttggtcat gtaaatgccg aactcgtcga 51900 cgctcagctt cgtcgtactg attccgcgca gttcggtaga gccgtcaggc agcgcaacat 51960 cctcgcagcc gataaaccag cgcttgaact gctcgtgcca gacctgatcg tcgaactgtc 52020 ggttgtcgac ccaggcaacc gatgcaagct cgcgtagaag ggaccagtag cgcttgttct 52080 gctcgatgga gcgcttcgac ttgagcgggc gcaggaccag ttcgtagccg ccctgagcgt 52140 cacgcatgag cccctggatg aggttccaag cggcgaggaa ggcaggacga atacctgcgg 52200 caccttgaat gcggaatgtg cggtcagcca ttgcgcgccc tccgctcagc ccgttcagcg 52260 cagtcccggc atttacgaac accagggacg atcgagcgcc gcgctaccgg gatttcctcg 52320 ccgcagtctt cacactcgtg caggctctcg ccgacgtact tgactcggga gtacaggcgc 52380 tcagcgagtt cacgctcggc gtagtcgttg gcgatatcgg cgatgtcagc caagggacac 52440 ctccatgcgc gcagcttctt tgcgcttgcg aatcagctcg gaaacgtcgt tggggtagtc 52500 gatctcggtt gccccgcatt caatcgcttt cgccttcttg ctgaggcaga tgtcgaagtg 52560 gcttttgatg gtcccaggga actggtgcca gcggcgctgt acgccgatct tgtcggccat 52620 ggtcagcagt tcggcatcgc tatccgcgaa catgtggcac atcttcatgc ggccataggt 52680 tgcgttcatg ttgtcgacgt aaacagccat cactcgaccc tcccttccga ccaaatgctc 52740 ttcacgacat caaccgggtc gcagtcttcc atcaagatca tcgtgaagcg cttggcgcct 52800 acgattacgg tccaagagcg tttcatttgg aggccctcat ctcttctgga tcggactctg 52860 cgcactccat aacggccggg aagtaacggt tgcgccacca agcgatgcct cgatctgaca 52920 tagacagctc gcgatcaacc gagcaacgat catcgttggt tcgcctatgg gtaagccgga 52980 ggtagtcctc cgcctcactc ctgcccatca tttcgagcag gacctcatca acgacttcgc 53040 tagctgggcg caggcaatcc agaatgtctt cacggaccga tagaattgcc ttgagccatg 53100 cgccctcccc cgcggctgta agaaatatct gacctaacca atcaagcgac atttccaccc 53160 actcctcgtt gcgcggaacc agcaggtaac aattcatgaa cccgcgcgtg tcgctctgtg 53220 gcctggaaac cagaaatacc actgggcgcc ccgtggactt acgcgtctga tctgctttgg 53280 ccacctcaat ctcggtcggt cgcgtgcctt tgacctcgag atagatatct gccgctggaa 53340 ggtagaaatc cggcaagtac ttgcatccct cgacttgaat aagatgcggc tcgtagagat 53400 agaagatgtc cgccgcgtcc atgagtcgag cccacatcaa ctcggtgtag gagcgcagtt 53460 tgtatccctg gtgctgatag atagtccgcc gcctttcatc acctttcatc accagtcctc 53520 cttctgctcg ggctgttcgc ggtagtggct tgcaagcggg acgaatcggg atttgctccc 53580 ctggaaggag gtgaatacgc tgccgatctc tccgtcccgg ttcttccgga tcaggatttc 53640 gccgataccc ttcctgtcgc tgttcgggaa atagacttca tcgcggtaca cgaacatgac 53700 gatgtcggcg tcttgctcaa tggcgccgga ctcgcgcagg tcgctgagga ccggacgctt 53760 gtcggggcga gactcgcacc ctcggtttag ctggcagagg ggaagcacag gacacccaat 53820 ctcccttgcc aacagcttca tctgacgcga catggtggtt acgtcatcta cacgcccctt 53880 gccatcgccc tctacgagtc ctaggtagtc gatgacgatc agccccaggt cgcccatgcg 53940 atgcttctgt cggcgggcga tggaccgtat gcgcggcatc gtcattacag gcacgtcgct 54000 cacggcgatc tttgcgtccc ggagcttgag gactgccgcg ttgagctcgg tgtaatcttt 54060 gtgagtgcag gaaccatctt tcaggttttg cagagagatg cctccgacag ccgcgatcag 54120 gcgatccatc aattgagcct ttgtcatctc aaggctgacc accagaacag gccttccctg 54180 cttgatggcc acgtctgctg cgatattcat tgccagggtg gttttaccca ttgcagggcg 54240 gccagcaatg acaatcatct gtccagactt caggccttgc gtgtattggt ctaggtcggg 54300 aatcccggtg ctcaaaccgt ccaacatatc gcctttctgc gctcggtcat ggcgctcctg 54360 aagcacctct acgtggtcgc gcagaatgtc tccaaccatt tggcactcac cggtagtacc 54420 acccgcatcc aaaccgagta caagggcctg agcctgagcg atcttgtctt cgattgagca 54480 attctgatgg gcaacctcct cgatcccgct ggctacatca actatctggc gcgagatagc 54540 tcgctcacga acgatccgcg cgtactcttt ggcattcgcc acgctgacga tgttggttag 54600 aatttctccg acgtaagcca tcgtgcgcgt gtcgtcgcaa aggaactctt tggcctctgc 54660 gagggtgatg atgtcaatcg gcgtgccggc ggactcgaga tcaagaatca gccggtacag 54720 gtctgcgttg acgctgtatg cgaacgcatc aggggaaagc tcttccgaca gaacgctgat 54780 cagatgaggc tgcttgagca tggcgccaag cacgccgtgc tccgcctcca ggctgtgaag 54840 ttcgatcatg cctgctcctc caactgtcgg aacacggcac gcgagcagat cacctcaagg 54900 cgcggcatga cattggctcc gcgataccag acctggctca agcgattggc ccgctcgaac 54960 acggtcttcc acagcgggct cgcctggtgc ttatcgctct cgttccagcg ctcgacgatc 55020 agggcgcgga gaaccttgtc accagccacc gaaacggccg gcaggttcgg acaggagcgg 55080 tggtacaggt cgatgatctt gtcgacagga acgccagcct cgctcacggc cttttcggcg 55140 ctccttgcca gccatttgac caggaacatg cgccagttct tcttggcctt gcggggattt 55200 gcagcggccc acacagcagc ccgagcaatc tccgcctcaa cgtcaaccgg agaatacgct 55260 ttagcccatt tggtaatcag ggctggttcg acttgaaagt cctcaccatc gaacgaaacc 55320 ccattggact tctcgacggg ctggtgatcg gccccctggg gggcggaaat ctgttccgaa 55380 ggaacagttt cagggggtag atcttttttc tttgtataga gaagggagtg agcaattttg 55440 gtctcactca cctttccgcc gattgagatc acattgtctg agtgagatga tttggtctca 55500 ctgagactgt ctttcttctg ttcgtggaat acccattcgc tggaaggaga aacaccaagc 55560 tcgccacggc ttcctccgat gcggaacagg atgcgcctct ccagcagatg gctgatcgcc 55620 ttggacacaa cgtcgcggcg catgttggtc agcgcgccaa tctcgtcggc ggttaggcgc 55680 tttgcctcaa cttgataccc aatcgtctgg cggcatatcg cgaaaagtac gcggaactcg 55740 cgggcaggca agtcaacctt ggccagcgac tccatcaagc tgttttccat ccgggtaaac 55800 cccccggtgt tgcgtaaaga aacgatattg ctcatactcg gtccgtccgt ttgctatttc 55860 ccaagcgtga ttcggctgcc accgatccac gcaccgacaa agccctgtag tagtcgctca 55920 gggctttgtt gtatctgcgc ctccactcac tcgaacccat acccgccagc tcttcagcag 55980 cgttagccat tgcggcgtag tcagaattcg tgagacgagg gcgcatgctc agacgctcac 56040 caggcgaggc ttgcgtcgca tctggtcaat catccgcaga gcctcttctg tcgcggcgcg 56100 agactcagag agttcacggt gagcctcttg cagctcacct tcatcagcgc catcaactag 56160 gctcgcaatt gcctgctgtg cttcgccgtt ctctttgatc agggatcgga gcatgcagag 56220 cacttcccgc tcgccgccct ctccatcgat caggcgaacc gataccccga ccggggtcag 56280 caggtcgccc aaggcctgaa tcttcaaatc gttcgggaga gcggacagga tcgacggcag 56340 gaaatttgcc ggaagcaggt tgttgtcctt cgtggagtca tccagccagc ggaacacccg 56400 atcggcattc gccttcatcc tgtccatcgc atcacgcgaa ggagggtcga atacgattcc 56460 ggtggcgata tgagcgttga tgcgttcgtg agcctccacg atgtgctgga ccacggtctc 56520 gcggctccag ccttcgcggc ggcgccattg gttcaccacg ccgagcagcg tggagatcag 56580 ggtgtgcgat tcgcttcgca tgctttgtgg cctcccggcc ggtagattgg atcgggttag 56640 gcggcggact gctcagtagc gaccttcagg gcgcctttcg taatgcgctc aatctcgtac 56700 tggcggagtt ttggaatttc ttctggccac tggcgcaccg cctcataggt aatgccgagg 56760 gctttggcta ccttcgaaac gccgcggaag tggctgatca cttgggtctt ggtcataggc 56820 gactccagtt cactcgcacc aattcaagca tgcttgcaat tacaaagcaa gcatgcttgg 56880 caagctacct tgtagatttc tcaacatgaa aaccacagac cggattacca agctcgtact 56940 cgccagaaag ccggagatcg gcccccgcgg ggtaaagcga gatatcgcca acacgtgcgg 57000 catcagctat gaggccgtga ggcaatggtt tgccggcgac actgaaaaca tcagaaatga 57060 aaatttgacc gctctggccg agggctatga cacgacggtg gactggcttc tatctggttc 57120 aggagagcca cctagacgaa aagcaacgag cagtgcggca gagaagttcc ttcaaatgtt 57180 gcaaggcaaa aagcttcgtc ccgatcagca gcagcgcttg gagcaggcag tgctagacac 57240 tctggatgat cagcccgtgg tggaggccgc agacaatgtg atcatcgccg acttctcccg 57300 caagccactg gtgggcgatg agattcgcat cgctcattac gatgttcagg gggcgatggg 57360 caatggaaag gttgttcaag atttcccaga gatgttccgc gatgtcacgg tcagccagca 57420 gcatctgcgc gaacttggcg ttaagtacaa ggacccatca catctgaaga taatcactgg 57480 cgacggacag tcgatggccc cgaccatcca gaacctagat ccgctaatcg tcgatgccag 57540 cattcgcgag ttcaccggcg acggtatcta cgcgttcacc tggcagggac tcttctatat 57600 caagcgccta cagttgaaag ggtcagacca cttcaagatg atctcggaca atacaagcca 57660 ccctccagag gatattcgag tggatgaaac ctacattcag gccagagtgt tgctggtctg 57720 gaacgcgaaa aggctgtgat gggcagaggc atcgcatcat aggcaaggtc atctggaggg 57780 gtggggattt gtagtcatgc tctggcgcgg cgctgtggct atggcagatt gtgggggagt 57840 aatgggcgca atcagagact ggacggaatg actcctgcac ctgaaatccg agcaaatgat 57900 ctggtaagag aacgccaggt tattcagcag aagcttcgag agactctaga gttcgatgag 57960 ctaagggcga agcggcttga gcggcagttg attattgagc gcgacaggcc tcgcgcaagc 58020 gacattatcc gtgctggcat gtggcatgaa ttggcctatc tgagcgcatt tgcagggcgg 58080 actgagcagg cactgagtcg gctggatgag acgcagcgta ttgggtttga tgatcttggc 58140 ataatacttt cgcgagcgtt catccttgag atgggtggac gtctcaccga agctcgcgat 58200 gtaattgaga tgcttgatgc tgctaacatc attgaaccat ccaggaaatt cctggtgcct 58260 cattacatgg agctgggcat gttcaaatcg gccacagaga ttgtcaccga catagaggag 58320 tacgacccgt acgccctggt ggcgaaagca attctcgaag aacatggcgt tgacgatctt 58380 gaagtgacga aaaggcttga gttcgccgcc tccatggtca tccaaagagt tggacatccg 58440 ctagttgact ataagctctt cgccatgcgc ggcgaaggaa ttctctatca gatcgtcgca 58500 aaaggcagca tagaggagct aggcaaactt ggagtagagc tgtcggatgc attggtcgat 58560 aacttcgatg gcgtattgaa cgagattctt tgcatcgatg taatcccatt tgttcctggc 58620 aaccagtcga ggcagatgga ggtgtttcgt gtcagtgtct agcgatgaca tcctgaggat 58680 tgcaaggtct ctacttggcg atgcagatga ggccttttcg cgaacatcca ttggacgctc 58740 ctactatgca gcctttcatg aagcgcgcgg aactgtcgaa agactttctc tcgctgcatc 58800 ccaaggaata ttaggcggat cacacgagaa gctgattggc gcttttgaag gaaagggccg 58860 cggtctggca aaaatcgcag cccgattgag gctgaggaag cttgccaggc agaaagctga 58920 ttacgatatc gacgaagaca tcacccccga agaagcagcg ctacatctcc accactgcga 58980 gctccttatt gacgacctgc ggcgtctaaa caagtcatga accagcccct cacccgcggg 59040 cttttcgacc cttgccacct ttgatagatt ccttccgccg gcctgggaag acagcagccc 59100 ggcaacaggc cgcgcctcga ctccagtgcg gccttttcac atcagccgcg catttgttac 59160 attgaggcgt ccttgaaggc acaacaccga aaggactagg ccgcgccgga gccttccccg 59220 gcgcggcctt ttcgttcctg cccttccctc ccggctctgc gctgagctga cgacagccct 59280 gccccggcgc ttgacgcgct acggctccct catagccgcc tcacattgag ttgtagtgcc 59340 actagcggta ttctttggcc tgtagcttgc tcgggagagc cgcatggccc gcacgaaggt 59400 tcctttctcc aaggtggcaa tgctcagcct ggcgctgagc gtttcgacct cgtgcgccca 59460 gttggcagcg gcaaccccca atctggatag tcagaagccc agcaagcaac atcagcagca 59520 ggagcttgct aagaaggcca agatccgcga gcgcatcaag cgcgccatgg ccgctctcgg 59580 ccaattgcgc gataccctcg aagcatcctg caaaatcatg ctggagcata aggtgcctga 59640 ctcgctgata aatgagcagc ccttcaccga ggtggtgcat accttgcgcc agctagaaga 59700 ggttgttcct gccgatagcg cactctcgag actgccagta atcggcgaag agtacgacgc 59760 ctttcgccgc aacctggcta aggttcgcgc catggccgtg cagaacgagg ttctcttcaa 59820 acagcaaatc accgttcctg aagtcttcca gagtgacgta agcggtgaag gactcaaatc 59880 tctggccgac ctcggcaccg aacgcctgca tcgcctggtg agctgatcac caggatggcg 59940 gtgattgtcg agttcaatcc agaaacctac gccgagctct tccaggacgt cctgaaggat 60000 ttcccttctc tccttgatgg tctctgccgc gattttgccc gctacatcga atctgatcgt 60060 ctctggctgc caccctattt cgggcgtgat gtgccatatg tcgtgccgca ggaggcttat 60120 cgcgccggcc tgatgcacat ccacatcgct attcctccca cggtattccc ggccaaccga 60180 cctcagcgtg acagaacctg cccgaacagt gctccgcaac aggacgccgc cctggtttac 60240 gtccaggggt tattcgagga aaaccgctac tccctgcttg ccctccttca ccctgatgcc 60300 catggtaagg ctcgccagcg cgagatgatg acctaccttg cccgtgtcgc cagccgcttc 60360 cgcgataaat actgatcccc ttcccgcctg acaccacaac caaagcccgc ctagcgcggg 60420 ctttttcatg gaatcagaat ggggtctcat cctcttccgc gccctcttcc acaggctcaa 60480 cctcgggaca gatagcttga tgctcaccct cgttcctaag cgcccaccgc aaggtcactg 60540 agccatcatc gttgaaaatc agctcaactc catcctcctc cgcaatcagc tccatcacgg 60600 cctcccacgc ctcgtccgta tcagtatcta gccggtgaac agtcaccgcg cgttctagct 60660 gcgccttcgg cgcattgatc attgccgaca ccctcagtcc taggcgatcc acagccgtga 60720 gttcctgctg gagttgctgc gctttcttct gcttggccat aagcccctcc ttgtactgtt 60780 cattcataca gtattaaaaa tcatcacaag attgcttgca ttctaaaaac aagcatgctt 60840 ttataaatgc aagccggctt gtgaacagca caagcaatac agcgaaggca caacaccgcc 60900 ggccaggcca ccgagccga 60919 <210> 2 <211> 627 <212> DNA <213> P. aeruginosa phage <400> 2 atgatcgagc agcgtagtga tgaatggttc gcacagcgcc tggggcgggt gacggccagc 60 aaggtcaagg atgtgatggc aaaggggcgc agtggcgccc cttctgctac ccgccagaac 120 tacatgatgc agctcctgtg cgagcgcctg accggcaagc gcgaggaagg attcaccagc 180 gccgcaatgc agcgtggtac cgaactggag ccgattgctc gctcggccta cgagttcaat 240 gcaggcgtaa tgacgatcga aacaggcctg atcatccatc cgcgaatcga tggatttggc 300 gcgtcgccag atggcctcgc gggggagcat gggctcgtcg agattaaatg cccgtctacc 360 gcaacccaca tctacacgat gcagtcgggc aagcacgacc cacagtacga gtggcagatg 420 ctcgcccaaa tgtcatgcag cggccgcgag tgggtcgact tcgtgagctt cgacgaccgt 480 ctgcctgatg aattgcagta cgtgtgcttc cgctaccacc gcgacgagga acgcattcgc 540 gagatggagt ccgaagttaa agcgttcctg gaagagttgg cagagcttga acatcagatg 600 cgagagcgca tgaggaaagc agcatga 627 <210> 3 <211> 450 <212> DNA <213> P. aeruginosa phage <400> 3 atgagaggtg ttaacaaagt cattctggtt ggtaacgtcg gtggtgaccc ggaaacccgc 60 tacatgccca acggcaatgc ggtgaccaac atcaccctcg ccaccagcga gagctggaag 120 gacaagcaga ccggccagca acaggaacgc gccgagttcc accgcgtggt gttcttcggt 180 cgcctggcgg agatcgccgg cgagtacctg cgcaagggtt cccaggtcta cgtcgaaggc 240 agcctgcgca cccgcaagtg gcaggctcag gacggccagg accgatacac caccgaggta 300 atcgtcgaca tgcacggaca gatgcagatg cttggcgcca agcctggaaa tgaccaggcg 360 gctcagagca ggccgtctca gcaggcaccg cagcagcgcc cacaggttgc gcaggattac 420 gacagcttcg acgacgatat cccgttctaa 450 <210> 4 <211> 516 <212> DNA <213> P. aeruginosa phage <400> 4 atgactgaat ggcgcgaagt ggttggttat gaaggactat accgagtatc agagcatggc 60 gaagtcatcg gggttatacg caaaaagatc aaaaagcaat tccccaatac tagcggatac 120 atgtcagtag gtctgtgcgc caatggcagg cagaagaaca ccacggtcca caaaattgtg 180 gccttggcgt tcctagataa ggccttcgag tcgctagaag taaatcacat agacggagat 240 aagctaaata atcatcactc aaatctagaa tgggttacgc gcttggaaaa tctaaatcat 300 gcaaaaaaga tggggcttct tagagagtcc accaaggtag tcgcaatgcc catagacggc 360 tcggttggat atttcttcgt atccatcaat caagccgtta agagtggatt taataacgga 420 aacatttaca actccataaa cgggaaatcc ccaaatcaca aaggcttcaa ttgggcgaaa 480 gtgcctagtg aaatgcagat aggtgaacag ccatga 516 <210> 5 <211> 435 <212> DNA <213> P. aeruginosa phage <400> 5 atgcgtacat cccaacgagg catagacctc atcaaatcct tcgagggcct gcgcctgtcc 60 gcctatcagg actcggtagg cgtttggacc attggctacg gcaccacgcg gggcgtcacc 120 cgctacatga cgatcaccgt cgagcaggcc gagcggatgc tgtcgaacga cattcagcgc 180 ttcgagcccg agatggacaa gctggtgaaa gtgccactga accagaacca gtgggatgcc 240 ctgatgagct tcgtgtacaa ccttggcgcg gccaatctgg cgtcgtccac gctgctcaag 300 ctgctgaaca agggggacta ccagggagca gcggaccagt tccctcgctg ggtgaatgcg 360 ggtggtaagc gcttggaggg tctggtcaag cgtcgagcgg cggagcgcgc gctgttcctg 420 gagccgctgt cgtga 435 <210> 6 <211> 303 <212> DNA <213> P. aeruginosa phage <400> 6 atgatcatca cattgtcacc gtactatccg ctgccaggca gcggcgaacg cctatcgctg 60 agcagggctg gcgatgtgct caccgtgaac ggccaggcgt tcgacttcac accgttaccg 120 gagggtggcg aactgccggc cgaggcgatt ggatcagagt ggttcgctgg tcccgcagtg 180 cgacgtgccg accggctgga actgagcctg cggttcccgc tggctgatga tgcaagtgcc 240 gccgctcgca ttcctgaacc gttgctgatc gatgccgatg gacctgtgga gttaccgcga 300 tga 303 <210> 7 <211> 3021 <212> DNA <213> P. aeruginosa phage <400> 7 atgacgacca tagctgagct tggcgtacgg gtgaactcgc aaggcgttga ccaggcggct 60 caggatctgg atcgcttggc tggttccgcc gtcagtgcgg aaagcgcggt tgattcagtc 120 ggagaaacct ctgcccaagc atccgcacgt atctccaata tggttcgcgc ctcgctagag 180 gctagtgatt accatcagag gcttgcgaag gcggctacca gcagtagcgc agccctcgag 240 aaggcgaatg cctcgaccat cgactggacc aagtaccagg aggagatcaa cgctcgcggg 300 caagccatca tccagtctca gcagcgcatt gccgaacagg ccaagaagtc cgctaccgca 360 gttcaggagc aatctaccgg tctcgatgcc ggcagccgga accttgccag gttcaacgat 420 cagttgggtc ggaccggcct taccgccagg caaacccagg ccgctatgcg ggggcttccc 480 gcgcagttta cggacatatt caccagcctc caggctggtc agtcgccaat gcaggtattt 540 ttgcagcaag gcggtcaaat caaagactcg tttggcggga ttggcccggc tctgcgggcg 600 gttggtgggt atgcgctgag cttgattaac ccaattaccg gattggctgc tgctgccggc 660 acgcttggct ttgctttcta cgacgcagag aaaaaggctg cctccttcag caaagctatc 720 tttgctggga atggcgcggc aggcatgact gggtcggctc tggcccaagt tgctaagcag 780 gctgcttcgg tctccggatc attggccagc gcgaatcgag ctgctattgc attggcagcc 840 agcggaaagg ttggggccgg ccaactccag agcctcacgg aaacgactag cgcaatcgct 900 caatttaccg ggcgggatat tgaggatgtg gcgaagtcct tgtcagagct gggggatgat 960 gcgactaggg cagcggcacg agttagcgag cagtatcggc tgctgagtta cgagcaatat 1020 caggcgatca aggcgatcga tgagcaaggc gaccatcagc aggctgtcga tcaactgaac 1080 gaggatctgc atcgtaacgc tcaggagagg ctgaaacagt atcgcgagtc tctgtctggt 1140 gttgagcagg gatgggacgc agttaaaacg gcgatcggta atgcctacgc tgcaatccgt 1200 gctgacttgt ttccaaccct caatgagcaa atacagacgc tccaacggac attggatcaa 1260 cggcaaaacg ctccgtttct gtcgaatgct ttgcgtggcg cactaactgg cgccgcaact 1320 ggcttgcctg gcgtggccgc taccggagca ctatttcagt cctttcggga tcagttcagc 1380 tccacagagg cattgaagga gcagaacagc ctcttgctcg tccgaaaaga cttgtccgag 1440 cagaatgcca agtcggaggc tgagctgggc gaggctgacc agcagctcat cgccattgag 1500 aaagagctgg gcgaccagtt aggcaacgtc tccccggcgg ccaagcgagc gaaagccatt 1560 gatgagctga ccaagaggta cgtcgccggc taccgcgcgg ccgagaagat gatctcggca 1620 ggcaagttga gcgcgcttcc cgactggctc aagggtgtga atattgtcgg tgatagcgta 1680 tcaggcggaa ccttcgacaa gctggtggct ggcatcaatc agcggttcaa ggacccgaag 1740 gcggccaggt cttctcaatt tcgtgatgat gctgctaccc agtacctgtt gcgtctgcgc 1800 gagcagcagg gagccctgga gcagcaactt ggtaccagcg agaaactgtc cgcttcgcag 1860 cgtgagatgg cgaagtggga gcagcagatt gcggacctga aggtgaaagc tgtcctgact 1920 gccgatcaaa agtctctctt ggctagggag gcggaggttc gcgcgcagct tcagaagaac 1980 gtggcgctcg aggccgaggc gaggaagaag gaggaaatcg ccaggatcga cgcgtaccgc 2040 gcaaaccttg aggggcgcct gcgctcagtg cagcaggggt acgaactgca gatcgctggc 2100 cttggtgcgg gcgatgaaga gcgccggcgc attcaggacc gtttgaagct ggagcaggag 2160 taccagagcc agagcgccaa actgcaggag cagcgcaacc gcggcgaaac caacggcggt 2220 atcagccaga gccagtacga aaaggaactc tctgctctgg acgattatca ccgtaaggcg 2280 ctggccaagc agaacgacta cttccatcaa gtcgatgagg ctcagaagga ttggtcgctg 2340 ggagccagat cggcgttcaa gacctatctg gaaagtgctc gggacgtggc gggccaaacc 2400 aagagcctgc tcaccaacgc gttcagcagc gcggaggact caatcgccaa cttcgccacg 2460 accggcaagc tgtcgttctc cgacttcgcc aagagcatcc tggcggacat ggcgcggatt 2520 gcaacgcgcg ccgctgcctc gcaggccctt tcgtccctct tcggcggctt cttcggcggt 2580 ggaaacgctg ccgcgcagtc gggtgtcgac aacctggtga gcaacagcgg gctgttcgcc 2640 aacggtggtg cgttcgccgg cggcgtgcag atgttcgcca ctggcggggc cttcaccaac 2700 agcgtggtca gcacgccaac cgcgttcggc atgagcggcg gccgcctggg tgtgatgggc 2760 gaagcggggc cagaggcagt gatgccgctg accagaacct cgtccggcgc cctcggtgtg 2820 cgcgctatgg gcggcggcgg ttcgcagatc aacgtcgagg tgaacattgc ctcggatggt 2880 tcggccaacg tctccagcag ccagcctggc ctggaccagt tcggtcgcga catcgggacg 2940 ttcgtcgagc agaaataccg acaactcctg gcgcgtgatc tgcggcgtga cggtgcgatc 3000 ggccgggcca tcaacgggta g 3021 <210> 8 <211> 981 <212> DNA <213> P. aeruginosa phage <400> 8 atggcacttt ccgatatgga ggtgttcaac acctatttca tgccggccac cgtcgagacg 60 ctgagccaga tggttgagcg attcaatgcg gcgtccggtg gcgcgatcct tctgaccact 120 gacggcttcg acggcgactt cctgcaaacc agtttctatg caggcctggc aggggctcgc 180 cgtcgcgtga accgctacgg ctcgaatgac gcagtaactc cggttgatct gacccagctg 240 aagcacaata ccgtcaaggt ggctggtggc ttcggcccgg ttcgatacga accatcccaa 300 atgacctggc tgcgcaagcc gactgctgaa ggtgtcgaag tcgcctcccg ctacttcgcc 360 gagtctcttc tgcaggatca gttgaacaca gccgttgccg ccctggtagc cgccatcagc 420 aaccaaggcg ccgctaccac tgtcgacgtg tccgatgcca agaaagtgga ctacattgcg 480 gtcaacgata gccacgcgct gttcggcgac cactctagcc agctcatcgc gcaagttatg 540 gatggtgccc agttccacac cttcattggc cagaatctga ccaacgctca gcaactgttc 600 caatccaacg gcgtgcgcgt ggtggatatc ctcggtcgct tgatcgtggt gaccgatgcc 660 ccggcgctct acaccccagc agtgaccgat ccggctgctc ctgccaagcg tcgcgtactc 720 tcgctgaccc aaggcgccgc aactgtccac gatgcccgag acctgatctc gaacatcgag 780 accagcaacg gcaaagagcg catcgagacc actctgcaga tcgactacag cttcggcgta 840 gggctgcgcg ggtatgcctg ggatgtagct aatggtgggg catccccgga tgatgccgct 900 ctgtccaccg gagccaactg ggacaaggtt gcaaccagtg tgaagcatac cgctggcgtt 960 ctggctgtcg gccaggccta a 981 <210> 9 <211> 417 <212> DNA <213> P. aeruginosa phage <400> 9 atggctgacc gcacattccg cattcaaggt gccgcaggta ttcgtcctgc cttcctcgcc 60 gcttggaacc tcatccaggg gctcatgcgt gacgctcagg gcggctacga actggtcctg 120 cgcccgctca agtcgaagcg ctccatcgag cagaacaagc gctactggtc ccttctacgc 180 gagcttgcat cggttgcctg ggtcgacaac cgacagttcg acgatcaggt ctggcacgag 240 cagttcaagc gctggtttat cggctgcgag gatgttgcgc tgcctgacgg ctctaccgaa 300 ctgcgcggaa tcagtacgac gaagctgagc gtcgacgagt tcggcattta catgaccaag 360 atcgaagcat gggccgctga gcaagggtgg ccgctgatga tacaggaggc cgcatga 417 <210> 10 <211> 210 <212> DNA <213> P. aeruginosa phage <400> 10 ttggctgaca tcgccgatat cgccaacgac tacgccgagc gtgaactcgc tgagcgcctg 60 tactcccgag tcaagtacgt cggcgagagc ctgcacgagt gtgaagactg cggcgaggaa 120 atcccggtag cgcggcgctc gatcgtccct ggtgttcgta aatgccggga ctgcgctgaa 180 cgggctgagc ggagggcgcg caatggctga 210 <210> 11 <211> 1341 <212> DNA <213> P. aeruginosa phage <400> 11 atgatcgaac ttcacagcct ggaggcggag cacggcgtgc ttggcgccat gctcaagcag 60 cctcatctga tcagcgttct gtcggaagag ctttcccctg atgcgttcgc atacagcgtc 120 aacgcagacc tgtaccggct gattcttgat ctcgagtccg ccggcacgcc gattgacatc 180 atcaccctcg cagaggccaa agagttcctt tgcgacgaca cgcgcacgat ggcttacgtc 240 ggagaaattc taaccaacat cgtcagcgtg gcgaatgcca aagagtacgc gcggatcgtt 300 cgtgagcgag ctatctcgcg ccagatagtt gatgtagcca gcgggatcga ggaggttgcc 360 catcagaatt gctcaatcga agacaagatc gctcaggctc aggcccttgt actcggtttg 420 gatgcgggtg gtactaccgg tgagtgccaa atggttggag acattctgcg cgaccacgta 480 gaggtgcttc aggagcgcca tgaccgagcg cagaaaggcg atatgttgga cggtttgagc 540 accgggattc ccgacctaga ccaatacacg caaggcctga agtctggaca gatgattgtc 600 attgctggcc gccctgcaat gggtaaaacc accctggcaa tgaatatcgc agcagacgtg 660 gccatcaagc agggaaggcc tgttctggtg gtcagccttg agatgacaaa ggctcaattg 720 atggatcgcc tgatcgcggc tgtcggaggc atctctctgc aaaacctgaa agatggttcc 780 tgcactcaca aagattacac cgagctcaac gcggcagtcc tcaagctccg ggacgcaaag 840 atcgccgtga gcgacgtgcc tgtaatgacg atgccgcgca tacggtccat cgcccgccga 900 cagaagcatc gcatgggcga cctggggctg atcgtcatcg actacctagg actcgtagag 960 ggcgatggca aggggcgtgt agatgacgta accaccatgt cgcgtcagat gaagctgttg 1020 gcaagggaga ttgggtgtcc tgtgcttccc ctctgccagc taaaccgagg gtgcgagtct 1080 cgccccgaca agcgtccggt cctcagcgac ctgcgcgagt ccggcgccat tgagcaagac 1140 gccgacatcg tcatgttcgt gtaccgcgat gaagtctatt tcccgaacag cgacaggaag 1200 ggtatcggcg aaatcctgat ccggaagaac cgggacggag agatcggcag cgtattcacc 1260 tccttccagg ggagcaaatc ccgattcgtc ccgcttgcaa gccactaccg cgaacagccc 1320 gagcagaagg aggactggtg a 1341 <210> 12 <211> 834 <212> DNA <213> P. aeruginosa phage <400> 12 atgaaaacca cagaccggat taccaagctc gtactcgcca gaaagccgga gatcggcccc 60 cgcggggtaa agcgagatat cgccaacacg tgcggcatca gctatgaggc cgtgaggcaa 120 tggtttgccg gcgacactga aaacatcaga aatgaaaatt tgaccgctct ggccgagggc 180 tatgacacga cggtggactg gcttctatct ggttcaggag agccacctag acgaaaagca 240 acgagcagtg cggcagagaa gttccttcaa atgttgcaag gcaaaaagct tcgtcccgat 300 cagcagcagc gcttggagca ggcagtgcta gacactctgg atgatcagcc cgtggtggag 360 gccgcagaca atgtgatcat cgccgacttc tcccgcaagc cactggtggg cgatgagatt 420 cgcatcgctc attacgatgt tcagggggcg atgggcaatg gaaaggttgt tcaagatttc 480 ccagagatgt tccgcgatgt cacggtcagc cagcagcatc tgcgcgaact tggcgttaag 540 tacaaggacc catcacatct gaagataatc actggcgacg gacagtcgat ggccccgacc 600 atccagaacc tagatccgct aatcgtcgat gccagcattc gcgagttcac cggcgacggt 660 atctacgcgt tcacctggca gggactcttc tatatcaagc gcctacagtt gaaagggtca 720 gaccacttca agatgatctc ggacaataca agccaccctc cagaggatat tcgagtggat 780 gaaacctaca ttcaggccag agtgttgctg gtctggaacg cgaaaaggct gtga 834 <110> Industry-Academic Cooperation Foundation, Yonsei University <120> Lytic bacteriophage specific for Pseudomonas genus resistant to          antibiotics <130> DPB154224 <160> 12 <170> Kopatentin 2.0 <210> 1 <211> 60919 <212> DNA <213> P. aeruginosa phage <400> 1 gccaggccac cgagccgacc gctctttaac aagtcagacc ccaccgcagt cccgacagcc 60 gcaggtcacc gcgactgagc gacggtggat aaacacgact gctgatgccg ggtaatcccg 120 gccaactcaa cgccaggcgt cgcgctccct cagctcagaa catcgagcag atagcgcaaa 180 gcgggctgag ggttgcactg ctaacgctcc ctgctcgggc catgaattgg cgcattcctg 240 ggcacagcgg acaggcctcg caaaggcttg cggtgaacac aaccaatagg aggaaacagc 300 ccatgaagca ctaagcccag ccgacgacac gggtcggcaa tccgcgcgta cgtgccctac 360 tcaacgggcc gccgggctgc actcaagcgc ggagtaacac tgatacccca tgaccagcgc 420 tgtatgccga ttgaaggcgt tgcgagggaa gcccaaggcc aaacacatca agtccgagct 480 gctatcggca gtggtgagga cacaccaccc gcgggttgta gaagcccagc aggcgaacgc 540 aggagtggga acgaaccccg acaaggagaa gcgaccgaga cgacccgatt tctcagatgc 600 ccttcgcaag aggggcatcg aagaagtcaa cacgcactgg aaggcaagac gatgaaccaa 660 gccaggcct atctgctgag ccagccatat tgcttccaaa tgggttttca agactttcgc 720 ggtggcgagc aatttgacag caggcggaat gccgaatggc aacgcggctg gcgttgggcg 780 gggcatccc 840 gaggaaagga catgatgatt ctaggcagcg ccaggcgacg cgtgcgcgcc aagcttcggg 900 cggagcggcg tgaagccgtt gtggaggccg ctatcgccgc attcacgact atcgagcgga 960 accgatttgt aaacgacgag agtgcggcgc tctacgacgc tgtcatcgcc cttctcaata 1020 cgccgccctg ccggtagcag ggcatcacca gacccaacac acccagcgat aagcgggaag 1080 agaggaatcc atggccgtac ttgtgatcct tgatgcgaat ccaaatgagc ccgaaggctg 1140 gcgatttcta aaagccgacg agtacgacgg agcggggcac tggaacgata acaggacgtt 1200 cccaactact gatgatgccg atgcttggat tcaaaagcat gcgcgcaacg gctggtacac 1260 gttgattgtc ggtgaagacg acgagtagca agccgcccgc gcctgccgga ctccccaacg 1320 caggcccgat ccacctggct ccccatcgcc aggctgtatc ggagagtggt ctgagcgcat 1380 agctgtagcg taggtgcgtc acagacgact gggttggacg gtgatgggtt ggccttatgc 1440 catcgaagct tccagctacg ccggagatca gcaccggcca gaccactccc ccatacagcc 1500 aatcacaagc cccaagggca agagaggaat ccatgccatc acttggcgag ttcgcagcgc 1560 tgttcgtggt gctgtttctg actatgtatt ggtgaggtga gagatgagtg agtggatcaa 1620 gtgcagtgac cgtatgccgg agcactcaga tgaagtcatg gtttgccgaa agtggccggg 1680 ccaggactgt ttcgctcccg agttcgaccg ctgggtatct gacgaaggct cggatgaagg 1740 cggtttctgg atgctggccg aggattcttg ccagcgcatc gaaacctgtg ctgatggacc 1800 gggccatgta gaacggcctg aaaccaccca ctggatgccc ctacccgaac caccgcaaga 1860 cgcctgacag gcaggagaac agatgatgaa gcacacgcaa gggccgtgga gcactaggtt 1920 agttcgacac gttggactca aagcaggttc gcatgtccat gttctaacgg accgcgaagg 1980 tttcaacatc gcgctgatct cttcgtggat agacaacaca gatacagcag aagaagcaat 2040 cgcaaattca cgcctgatcg aagccgcgcc cgagctgctg gaggtcctgg tcgctctggt 2100 tgagtgcgag caaacgacac cagagctttg ggaagcagcc cgagccgcaa tcgcaaaggc 2160 caccgcctaa cgcgcccttg cgcatacaca cactggaggc gacatgagcg agtggatcag 2220 tctcaaaaag gagcgtccgg gcgatgagca tgatgggcgc tacctgatta tttacacatg 2280 gagcagcgca aggctcaact tcatcgttga ggccgacatc tggcttggca gtcaattcga 2340 attttgggga gacaaggtat cccactggat gttgctacct gagccgccag acgcctgact 2400 tccccggcaa ggacgccagc cttcaatggg gatgatgcgg agtgatgatc cgcagagagg 2460 caatctcgct cggaacaatt tgccaagcac tgacaatggt cagccgtttt agccgagcca 2520 gccggacata tccccggcca tccccaccct acccctctta gcccggcaag tccgggcatt 2580 ttttcgcctg tatgcgcatg cgccctgaac gaatcgtctt cgggagcggg gcttatgacg 2640 aggcctacgt ctcttagggc gcagccgcat gcacgcgaac gcgaggtgaa atatgaacac 2700 cgcatttcga tgcgcccagt cgttacatga cgacgcgact cctgacgaca cccctcccgc 2760 cgctaactcc gatgagttct gcgactgggc agaacacgca gtcaacgatc tgcggtgcgg 2820 catggacgtg aagatcgaaa ccatgcgcga gcgtgtcgtg gtattcgcca gcacgctgac 2880 cgagcgggta caggccgaac tgctgaagct cgtccaggcc gacgaagaat gctggctggc 2940 tcagatgttc caggccgccg aagacgagtt cacctctacc gcccgcgagt gcgcggcaaa 3000 ccttgagcat caccagggaa tcactgaacg catcgcgctc ggactcctga agccgcacgc 3060 ggacctggtg ctggaaatga tcgcagagca gaacatggag gatgcagcat gagcattgac 3120 tggaccaagg cacctgaagg cacaacgcac taccacatag gtgaagacat aaatccttgg 3180 cgaaaaatcg aaggtactgt tgcgtacgag cactacagag gcaaatggct cagggtcaac 3240 agtttcaacg aaggatgcat gcctggctat tacgtaccta ttccgcaaga gacctgggac 3300 ggccagggac tgccgccggt tgggacggtg tgtgaagtca agcaccgaga tataggctgg 3360 gttagatgcg agattgttgc ccacaaatcc tttagttgtg gtggccttac ccatgcaatc 3420 gcatggatag acgaaaacac ccttgatcaa tctcaagggt tgcgattccg ccaactccgc 3480 acccccgagc agatcgccgc cgaggagcgg gagaaggcag tcggtgatat ggctatgtca 3540 attcaaggag ttccatatca gtaccctacg ctttacgcgc tatttgacgc cggctaccgc 3600 cgccaggagg aagggaaatg acaaccccta tcgtgcaatc gatcagtgat gagcaattgg 3660 cggagttgga agagtactgc cacaagaggg cattcgtctg ttgtggcaat ttcaaatccg 3720 gggccgaata catgggcgcg cgcgaggaag tctgctgtaa cgagccagtg ttgacggatg 3780 taaatatcaa cactccagca gaggagatac ttggcctgat cgctcgcctg cgcgctgctg 3840 aggcttatgc taagcgctgg cgtcatgcgc ggaacatcct gaccgtcgag gcgattgagt 3900 cagctcaatc tgattacatc aacttcggtt tgccgcctgc tgaaagcgaa agcatccgcg 3960 cagataaggc catcgacgcc gcgatggagt gcacgctatg accatcacca tagacctgaa 4020 agaggccgcc aagacaacgt tcttcgcggc ctttttcttg ggcagcatcc tggccttcgc 4080 cgtggcgttt gtggaggtgg cggggctatg agcggaaaga aagcagctaa gcgcgcacat 4140 gctgtagcga tgcgtgccgc aaagcttcgc cgggacggct gtagcctgtc cgcaatatcg 4200 gaggctacga gcatcccgcg cgagcaaatt gaatctcgta taaagcttgg cgaacgtctg 4260 ctacagcttg tcgaaacgga gtttgggcaa tgagcacccg ccgcacggcc atctggctag 4320 gcagcctctt cggaggcctg ctgtacctct tcatcctggc agccggcccg atctggggcg 4380 gcatcatcac cgcagaagct acgcacctgt ccgcagcagg cccatagggg ataactgcgg 4440 cttccccagc gggcggtggg cggcatgaag aaaacacccg cagcagcggc ttctagcgca 4500 acgctattca tcccgcagag gtgacgctgc cgagtggcgc cgtaagcgcc tttcaccttc 4560 tacctggaga acgatatgaa catctacgaa tgcgaacgcc ttgcgcgtga tcttggctac 4620 gatagagcga agttcacggc aatcttcccg gccggcccat tcgaatgcca gtggctggac 4680 gcctacatgg gaatcttcaa ggtcgacgct gacgggatgc gtgacggctt cgtcatggtc 4740 aaggaaatgg ctgagatgtt cccgaacttg gaatgcattg acctgcgcgt cgaagacgac 4800 gtctaacact cccttcactg gctgcgcatg cgcggcgagg atcattcatg tccgcagaaa 4860 accaactggt cgaagtacca gccaaagaaa ccgctctgca agtctactcg gcagacaatg 4920 gcctggatcc attcctggcc aagattcgcg aagagatcga cggcttcgtg ccggatgtga 4980 ccactcgcaa gggccgagag gcaatcgctt ccatcgccta caaggtagcc cgctccaaga 5040 cggcgctgga caacgtgggc aaggaattgg tcgctgagct gaaggaggtc ccgaagaaga 5100 tcgatgccga gcgtaagcgg atgcgcgatc tgttggattc ctggcaggcc gaagtgcgca 5160 gtccgttgac cgagtgggaa gaggctgaag cggcgcgggt tgcgcgtcat cagggcgaga 5220 tcgacaagat aaaccttcgc ctggaatgcc gcgatctgga ctctaatgaa ctcaaagcca 5280 acatcgcttg gttggaaggc ctggccataa gtgaagcctg ggaagagttc gaggagagg 5340 ctgctcgcgc caaagataag gctttgatcg ctctccgaga agccctggtt gcccgtgaga 5400 agttcgaagc cgagcaggcc gaactggaac gcctgcgcgc cgaagcagca gcacgccagc 5460 agaaagagcg cgaggagcgc attgcccgcg aagcagcaga gcaggcacgg cgtcaggaag 5520 aggccaaggc ccaggcagaa cgcgacgccg cagtacgccg tgaagccgaa gcacaggccg 5580 cagcagagcg ccgcgaactt gaacttaagc ttgccgccga gcgcgccgaa cgcgaagcca 5640 ttgaagccaa gcagcgcgca gaacaagcag agcgtgatgc gcaacgtcgc gctgaagaag 5700 ccgcagcggc agaacgcaaa cggcaggccg atgagcaggc ccgcatcgaa cgcgaggctg 5760 ctgcacgcga agccgacaag gcgcacaaga aagccatcaa caacgaagcg ctggcggctc 5820 ttatcgccgg tggcatgccc gaggaatgcg ccaagcaggc gatcaccctg atcgctcagc 5880 gcaaggttcc tcacatcacg atcaactatt gaggttcaca tgggaactgc actaacaccg 5940 ctcctgacga agttcgccac gcgctacgag atgggtacaa cgcctgaaga agtggcgaac 6000 acgctcaagc agacctgttt caagggccag gtcaatgatt cgcagatggt cgccctgctg 6060 atcgtggcag accagtacaa actgaacccc ttcaccaagg agttgtacgc attccccgac 6120 aagaacaacg gcatcgtgcc ggttgttggt gtggatggct gggctcggat catcaacgag 6180 aacccacagt tcgatggcat ggaattctca atggaccagc agggaaccga atgcacctgc 6240 aagatctatc ggaaggaccg cagccatgcc atcagcgcga ctgagtacat ggccgagtgc 6300 aagcggaaca cccagccttg gcagtcccat ccgcgccgga tgcttcgcca caaggcaatg 6360 attcagtgcg cacgcctcgc gttcgggttc gccggcatat acgaccagga cgaggccgag 6420 cggatcgttg aacgagacgt cactcccgca gaacagtacg aggacgtcag cgaggcggtc 6480 tgcctcatca aggactcccc aacaatggaa gacttgcagt cagcattcag caatgcctgg 6540 aaagcctaca agacaaaggg cgcgcgcgac cagcttacgg cggccaagga ccagcggaag 6600 aaagaactgc tggacgcccc tatcgacgtt gaattcgagg agaccggcga tgatcgagca 6660 gcgtagtgat gaatggttcg cacagcgcct ggggcgggtg acggccagca aggtcaagga 6720 tgtgatggca aaggggcgca gtggcgcccc ttctgctacc cgccagaact acatgatgca 6780 gctcctgtgc gagcgcctga ccggcaagcg cgaggaagga ttcaccagcg ccgcaatgca 6840 gcgtggtacc gaactggagc cgattgctcg ctcggcctac gagttcaatg caggcgtaat 6900 gacgatcgaa acaggcctga tcatccatcc gcgaatcgat ggatttggcg cgtcgccaga 6960 tggcctcgcg ggggagcatg ggctcgtcga gattaaatgc ccgtctaccg caacccacat 7020 ctacacgatg cagtcgggca agcacgaccc acagtacgag tggcagatgc tcgcccaaat 7080 gtcatgcagc ggccgcgagt gggtcgactt cgtgagcttc gacgaccgtc tgcctgatga 7140 attgcagtac gtgtgcttcc gctaccaccg cgacgaggaa cgcattcgcg agatggagtc 7200 cgaagttaaa gcgttcctgg aagagttggc agagcttgaa catcagatgc gagagcgcat 7260 gaggaaagca gcatgagagg tgttaacaaa gtcattctgg ttggtaacgt cggtggtgac 7320 ccggaaaccc gctacatgcc caacggcaat gcggtgacca acatcaccct cgccaccagc 7380 gagagctgga aggacaagca gaccggccag caacaggaac gcgccgagtt ccaccgcgtg 7440 gtgttcttcg gtcgcctggc ggagatcgcc ggcgagtacc tgcgcaaggg ttcccaggtc 7500 tacgtcgaag gcagcctgcg cacccgcaag tggcaggctc aggacggcca ggaccgatac 7560 accaccgagg taatcgtcga catgcacgga cagatgcaga tgcttggcgc caagcctgga 7620 aatgaccagg cggctcagag caggccgtct cagcaggcac cgcagcagcg cccacaggtt 7680 gcgcaggatt acgacagctt cgacgacgat atcccgttct aaatcaacaa gttacgcgaa 7740 attaaaggcc ctgttgaggg ccttttcttt tgcccggaga aagccatgga aaccgacatt 7800 cccgagattc ttagcgacct gagaataggc gctgatgcgt ggtccggcgt gcaagagccg 7860 gttgcccatg cgctgactca cgatgacatt caagacgcag ttgctgagta cctggcatcg 7920 ggaggggtca tcacgaatat ccccgctggc gtctcttcaa atcagccggt cacgttcaat 7980 agccgcatta ccggagcatc taccggaatg gagcgagagc agcagaagcg tgttcaggcc 8040 aagcgcacgg caaaggacat cgaatactgc cagacgctcg aagacctagt gatcctagat 8100 tgcggtcgat gggagatagg ccctgccatg gggataagcg atcacaccgt acagcgactg 8160 cttcgcacct atttctccac ccgcgccgag ttcgacaagt ggagggcatc cggacatggg 8220 aaatcgacgc tcataaacgg cgagaaacca tgctcgaagt gcaagacggt caaacctcta 8280 tctgagtact actcgaatcc gagcaagaag gacggccatt gcagcgaatg taaggcctgt 8340 gaaaacgcgc ggaggcgagc agcaaatgca aagcaagcgg cttgagttcc ccgaatcggc 8400 agaagaatac cgcgagggcg tcgacgcacg cgaccgcggc gaacgtctcc aggcctgccc 8460 ctacggactg cacatgctct atgagcggtc actttggcta gcaggacacc acgacagaga 8520 catgggcata gccccgaggg tagcagcatg agcctgcacg aacacggctg tttcgccgac 8580 agctaccagg tccgacatat caacgcgcag tgcgtcgtcg ggaaggtctt ccggcacaag 8640 ccgactaatc gcagatacat cgctgttctc gaagccggcg gatcagttga gcttcaagag 8700 acagcgggc acagcacgta cacatcaatc gaagcgctcg gcaatgccga ggtgtgggag 8760 gccgttaaat gagcatggaa atgaacaaag cgctggacct tctgcgcgaa atccgcccga 8820 gcattccgaa ggaagtgcta gagctttggt gcaaggaccg cgatgcattc atagcatcgc 8880 atcctgcggc agagcaggca ggcggggatg agcgcgcggc gtttgaggct gcttttgctg 8940 caatgggtag gccggtatgt cgtgctgatt acgaccaaga cgcctacgga accccattcg 9000 atgacggcgg atggactggc tggcaagccc gcgccgccct ggcgcaaccc tccccggcgc 9060 aggccgagca ggcagagccg gagcggccgg aggttgtggc gtggcaatac cgcgtcaccg 9120 caggcccgca aactggctgg agtctctggc acccaggaaa aggcgaggag ttcgaacgct 9180 cctacaccgt cgaacgccgg ccgcttatga ccgtcgccca gtacgaccgc atcgtcgggg 9240 agctgcgggc ggtgatcgcc caactccgcc agcacaagaa cgattacatg gattccggcc 9300 aggaaactta ccgagccttg cagaacgaaa tccgggagcg ggaagcggaa attgctcgtc 9360 ttgatggtct ggtttcgggc cgcacggcag agcgcgacgc cgctaatgct cgcctgcacg 9420 aagtagcaac agcctgcgca acggcagagc aagagcgcga cgccgccctg gccagggtcg 9480 cggagttgga gaggcaggag ccggtggcat ggatgcacga tcagccaaac cgcgtcgatg 9540 tcatccatcg agacgtcaag gatctgctac agcgcgtgcc gggcagtagt agaggaatcc 9600 atcgcccact cgatgtcagc gagcattaca cgattccact ctacgccgcc cctgtagccc 9660 aggctcagca cagcgtgccg gaggggtggg tgcaatcact gccgctaaag gatcaccagc 9720 cttgcaagcc gaacgaggat agagcgaacg gttacacaat cccgatctat tcaaggccgg 9780 ttcttgttga ggaagccttg cgtaagttac gtgctgtcct ctgcgaccca attggaaacg 9840 ttgtcattga cggcagtgat ggtgaccgag aagaggtaca gcgagcgctc ggtatgctcg 9900 ccgccgcgcc cggcaaggag gggaacgatg actgaatggc gcgaagtggt tggttatgaa 9960 ggactatacc gagtatcaga gcatggcgaa gtcatcgggg ttatacgcaa aaagatcaaa 10020 aagcaattcc ccaatactag cggatacatg tcagtaggtc tgtgcgccaa tggcaggcag 10080 aagaacacca cggtccacaa aattgtggcc ttggcgttcc tagataaggc cttcgagtcg 10140 ctagaagtaa atcacataga cggagataag ctaaataatc atcactcaaa tctagaatgg 10200 gttacgcgct tggaaaatct aaatcatgca aaaaagatgg ggcttcttag agagtccacc 10260 aaggtagtcg caatgcccat agacggctcg gttggatatt tcttcgtatc catcaatcaa 10320 gccgttaaga gtggatttaa taacggaaac atttacaact ccataaacgg gaaatcccca 10380 aatcacaaag gcttcaattg ggcgaaagtg cctagtgaaa tgcagatagg tgaacagcca 10440 tgaccgaaga agaacatgat gccaagctgc gcgccgaggc ccaggcgctc agggaggaag 10500 tcgcgcgcgg aaaccggatt acgttggcca tggcgctgga tatcgctgcg gtaggtgtag 10560 cacttgggat tcccgagag caacaggaag gtggaactgg tgaattcatc gaggccatcc 10620 aaagccttca gaaggaactg gaagccctgc gcgcacgggt ggtggttccg gatgggtacg 10680 cgctcatgcc gctggaacca tcccccgaaa tgcgtcttgc gagccaccgg tacaagcgca 10740 agaacaaagt ctcgaccgga cctggattct ggcgcgcaat ggccgaggct gctccgcgcc 10800 tcaacggcct gacggtcagc gaggggctgt tgaggctggc cttggagttc attatggcaa 10860 ctaactgcca gggctctatc ccgcttgggc tgattgaaga acttcgcgcc ctgctcaacc 10920 aggacaagga gaacggcgac catgctgcat gagccggagg agtaccgatt gttcagtcta 10980 tggatgctgg tcttcatggc catcggctgg tttggtggct ggatacacgc ccattacacc 11040 gtagccgaag aatgccggaa gctcggcaag ttctacgtcg gcaagaccgt attcgagtgc 11100 aaggcgatca ccgaggaaga caaggagaac ggcaatggct aaacactatc ctcttgaggt 11160 gcagagcgtc ggcagcgaca cctacatcgc aatgagcaag ggacaccacg acctcgaagt 11220 gttcatggcc gaggccgtca aggagtgccc gggtcggttc ttgggcggcc cgcagcacaa 11280 gtggtgcaag acggttccgg accgctcggg cgagtttgca catcggtatg tgttcgtcga 11340 ggaaggcacg ccaggcgcat ggccggcgac ctactgctgg gaattcggcg aggactggaa 11400 acgctggaat gggattggcg agcagcaggc atagccaccc atcgccaacc actgtacgca 11460 ccgatgccgg aatcccggca tcgcttacag gccgccttag caccagcctg aaacccgcat 11520 ggttactggg tttccgcgct taaacacagc tacttggcac caccttacag gccaccccaa 11580 accaacgaat ccgcccccgg aggaccaacc gtggacaacg aaaacgaaac cctggtcgca 11640 gtgatagtca tcgttctctt cgtcctggga gtcttccggg ttgtcgggga cttccagaac 11700 ctatacgagc agacagaaca gaaaggacag gagttgagca gatggagcaa gaattgaagc 11760 catgccccta ttgccgaggc tatgacctag agcgtcgctg gtgtcacgtt tgcaatggca 11820 gtggcgtcgt tgatgtcaag gctcaacagc gagagcgcgc agagattgta aaggcgctgc 11880 gcgaagccgg aattgaagtg agggactgac cgtgcctgac atgagagaag attttgaaga 11940 ccgcttcccg atccctgaag gtatcgagtg gcgtgacacc gattacttcc cgatgcagac 12000 cgataacgtc cacgtatacg tggctcttgc cggagtcgct gcgcgctaca cgtcgatgtg 12060 gcaagcctgg caagccagcc gcgcggctct gagggtggag ttgccggcaa aacgctcata 12120 cagcatgtat gcaacgaagc atgaatgtca tgcgttcaac gatgcgatag agaaggctaa 12180 cgaagccctc cagcaagccg gaatcgaggt ggcgaaatga gctacagcgt ggagaaagtc 12240 atgcgcgtct atgacgacaa agaaggcgtg tacatcgagg tcagacagca cccggatgca 12300 ccggacagcg gcctggaaat ccataccaca ggaaaccagg cctgcatcga ctggtacggc 12360 gagcagcgaa tcgtgctgaa cagccgggag cacgctcttg ccctggcaag ggccatcacc 12420 gaaatggcgg agatgatccc atgaccgaag acaagccgga atcgaggtga agcaatgagc 12480 gactatcgag tttggtgccc tgactacggc caggaagaag aagacgcgat gcacatccgt 12540 gattcgtacg accatgctgc cgcagcatgt aactgggccg agcaatatga gcggagaaat 12600 gctgactaca acatcgccga tggcgggtgc gtgacggtaa tggtccatcg cctcggaggg 12660 gatacgcaaa ccttcgcggt atctggatat gcacggccaa tctattccgc aaccgctatc 12720 taggagcaac catgagccga ctgaccgccg agcaagcgcg agatatagct cgcgaacaag 12780 accctgcgtt cgccgtagat accatccttg caggcatcgc aaaatcagcc gccgaaggca 12840 agtacgtgta caccacccgt gactatgggt tcggcaccag cacctactgc aacgaatgcg 12900 attacccgaa gctctgcatc gcgatcctga aggaactgcg cgggctcggt tacgtctgcg 12960 ctgtgcgagc cgaagaacgc ctgttcgttg acctgtggct cgaagtgaaa tggggagaaa 13020 agacatgacc gaccacgcag agctgcggag gctggctaag gcggcaacgc ctgggccgtg 13080 gagttgcaat cgccactggg caattgtggg aggaccaact cttgagttca cgaacggtgc 13140 agcgcagcag cagatagcca tggcctgcca gcaaagctgg atgcgtgaag aagaactgcg 13200 caacaacgcc gcattcatgg ccgcagccaa ccccaagacc atcctcgccc tgctggacga 13260 gatcgacggc ttgcttgctc agcatggccg cgatagctcc gaacttaggg cgctctgcca 13320 agcacgcgat gatgctagga aagagcggga caggctcaag gcggagaacg aggcgctgcg 13380 gggagcgcta caggcagtag tggatgatcc aacctggcgc agcaacgaca acaccctgtg 13440 gccgaagatc atcaaagcaa tgaacccagc cgggcgccac tagctctccc tgagctaacc 13500 cggctgggcg ttcaaatcct accagaaggc ctgaccgagc agttaacccc catattgccc 13560 gatgcgggcg ccctgcccgg ccaagcctcc acgaattcta accgccaacc cgatgccgtt 13620 gatcggccaa ggtctcgcta tgtctttgat ttcagttgag gcggccgccg gcattctcgg 13680 cgtgagccgc aggaccgcgt accgctacgc ggacgaaaag ctgatcccgg tggtcaggtt 13740 caaaaagaca atccgggttc acaaggaaaa gctcgaacag atgcttgaag aggaagccgc 13800 tgctagcatg cgcgacgcgg tcggcgtacc ggaggaagta tgccgtacaa gagaaacgac 13860 tccgcctact ggtggatctc tttcaaatca gcaacaggaa agcttgttag acgctcttct 13920 ggaactgccg actactcggc ggcgaaagca ctagagcaac aggagcgcgc gaaagcgtgg 13980 aaggaaaagg aaatgggcgt gaatccgccc aggacctttg aggaggtgat cattccgtac 14040 ctgcagcacg ctcgccagca tcagcgcagc tacgaaacga ccgtgcaccg cataaagccg 14100 ctgcgcgagt attttgccgg acgcgtggtc aacgatctag ggggccagga catacgggga 14160 tacggttcgc acagattgga tgccggcgca tccccggcaa ccattaaccg cgaactcgct 14220 gccctctccg cggctatcaa ccactgcaac accgaactgg agtgggccct tcctaacccg 14280 gtgaaggggc ggaagatgcg cgaggccgag gggcgtgatc gttggctgac cagggcggag 14340 gtcgaggccc tgtgccgcgc cgcgcgcgtc cagaagtttg gcccgatgct cgaggatttc 14400 atccgcctag cggtaaacac cggatgccgg cgggaggaaa tgcttggcct ggagtggcgc 14460 agagtggatt tcgccaatcg actgatctac ttggaggcat cccacacgaa ggcaggtaag 14520 cgccggagca tcccgatcaa cgaaggggcg atggcagcac taaagcgacg aatggcattc 14580 aggtccgaga acagcccgga atgcccctgg gtctttgcgc gcgctaacgg tgatcgagtg 14640 gtatcgcttt cagccggatt caagcaggcc tgccaggcag cgaagattgt ggactttacg 14700 attcacgacc tgcgccacac ctgcgcggca tggctggtca gcgccggcgt tccgttggcg 14760 gatgtacggg atctgctcgg acactcgaca gtcgcgatga ctgagcgata tgcccatctt 14820 gctccggcca gggtaaggga tgctgttggg gttcttgatc aagtccgtga aagccgaatt 14880 tcacgttctg ttcacgctga taatccagcg catctacatg gagggccgct gaagctcgta 14940 aacacttgat ttagaaggtg gtgcggacgg agagactcga actctcacgc cttgcggcgc 15000 tggaacctaa atcctgtctc gcacctcaga agcgcttata ttacaacagt ttacgccgac 15060 cgcaatcact taaactgtgc caatcgtgaa attccttttc acgttttcca tttccgcgct 15120 tcacgtttcc gtcacggcca gcattcagcg gtccgactcg taagccgcaa caccgctacc 15180 gacagagcgc cactcatcct gcggcatgcg cgaatcacag atgaatacct cgacctcccc 15240 gccttctttc ggctccgcag gccgaatagc agcatgccgg agaatcgtct ccatgtccgg 15300 ccgtagctg ctctccgagc cgtggaacga ccagatgccg aacttgccag cgctgcccac 15360 ctggtggtcg agcttcaccg accagccctt gaatcgaatc accagcatca ccgagctccg 15420 taggaaaagg ccgtagtcta ctcctaatcc tgacaggcct gattcgcagc caggagctgc 15480 gcctcgtaac cgatccgctg caagcgttcg gcgagcaacg cgcggacctt ggtctgcaag 15540 tcgtcgcctt ttcgcagccc agtagttgcc caagccggca cctccaccgc cggcacccgg 15600 ccggcaccg ccactggcac ttctacgcgc accgtgcgcg gctcggcttc ctgcctggcg 15660 gcgcatcccg ccagcgcgac cgcaacccac aatagagcaa aacctgattc acctctcatt 15720 gcccttcctc gacttgatat ttcggtcgtt tagctgtcta tactggaaat gtcacttgac 15780 atgcccaata tggacgggat aatcgcggtc caccggggga atcctgtgga taacttgtgt 15840 aagccagagg aggcgccatg aaaccagtcc aattccttct cagagggtat gcggagcaca 15900 aggatggcgt atggcaagcg ttctgcatcg atctgtgtct ggcagtacag ggtgagtctc 15960 gtgaagaggt gatccgtaaa ctccacgagc aaacctacga ttacctgaaa gacatcttcg 16020 agggtgaaga ctacccatac gccgctcagc tcctcgcccg caaagcaccg ctggtgcaac 16080 gcctgaagta tcactaccta gcatacaggg agcaggtcag ccgactgcgc gatgtgttca 16140 ccttcaaaga cgccatgcct cttaagctgg cgtaaatggc aaggctccac cccgtcacat 16200 gcaaacaggt caaggcagct ctaaaagcga tggggttcga gccaaggcca agaacgggaa 16260 catctcacga aaagtgggtg aagactgcgg gtagcaaccg atggatagta acagtcgatt 16320 gccccaaatc tcccttcagc aatgacctga tcgcctccat ggccagacag gctggaatgt 16380 cgacaaaggc attccatagg aagtgctgcg aattctagcc ccgccatcgc ggggcttttt 16440 acaatcccag ttcccgatca atcacctgtt cagtcgcacc acactgctcg ccggcggtgc 16500 gatcacgcag cagacggttg gcggcggaat actgctcggc ggcctgctgc cgcccctgct 16560 ccagcgcatg ggctgcctcc ctggcgcgct gctcaccagc ctgacgcagc gcggcaatct 16620 gcccgccctg ctccactact gcggcctcca ggctcccacg agcggaacgg caggctgcca 16680 gatccgcctg cgcggcatcc aactgcggcc ggtagtgccg cgctccgatc cagacaccgc 16740 cggcggtgcc gaggccgacc agcagcaggc aggccagcgc gaccgataaa gcgcgagcgg 16800 agatcacgac agcggctcca ggaacagcgc gcgctccgcc gctcgacgct tgaccagacc 16860 ctccaagcgc ttaccacccg cattcaccca gcgagggaac tggtccgctg ctccctggta 16920 gtcccccttg ttcagcagct tgagcagcgt ggacgacgcc agattggccg cgccaaggtt 16980 gtacacgaag ctcatcaggg catcccactg gttctggttc agtggcactt tcaccagctt 17040 gtccatctcg ggctcgaagc gctgaatgtc gttcgacagc atccgctcgg cctgctcgac 17100 ggtgatcgtc atgtagcggg tgacgccccg cgtggtgccg tagccaatgg tccaaacgcc 17160 taccgagtcc tgataggcgg acaggcgcag gccctcgaag gatttgatga ggtctatgcc 17220 tcgttgggat gtacgcattt acgggtctcc aaagacgacg aagcccgctc aatggcgggc 17280 ttatcttcgt cgggaatgtg ttcgggtcag ctaccggtca ggatcaccaa cagcacggga 17340 gacgacagcc aggcggcggc tccacaggcg aggatcagca gactgacccc gatgcaaaaa 17400 ttcaggaaat gactcgttgg cattttgacc tccagccagt ctttaacctt cagcaagatt 17460 ggtctacgat tcacgtatgt tctgctcctt gtccttccca aggggtggaa ataaaaaccc 17520 ccggcacgct gtgaacgtcc gggggttttg cttttctgat tctgtcttta cttttctgta 17580 accctgcaag cgatctcgac catctccctg ttgaagcgag tcgagtcggc aagaatcacg 17640 ctgctgtcaa gcacggcaaa cctagtgaag cctgtgtatc caccatagct gttcttcgca 17700 ttcaccttgc cgcagatgga gtatttatct ggcggggctg caatcgaacg aacgccaatc 17760 aatccactga actttgcgga gtccgggtct ttcaagacct ctcgaacgga cgccattgca 17820 tgctcacgct gctggtcgtt cagctcaaac gatacggttt ttggctttgg ggcctgcacc 17880 ttgggagctg ggggtggcgg agtcgcacag ccgctcaatg ccgcaatgca caggacaata 17940 caggtcatgc ttttctggaa catttggatc ttccttccgt tgagaccgac gaaacatagc 18000 atgttgccat cccttcgacg ccttgacact gctgtacgcc tgaaccatag tctgcctgcc 18060 gctgcaaatt cagcggtcgg gcttggccgc ccgaatcggt aaggcgcaca gcgccgcagg 18120 gcgttttttt gtgccctcgc tttatggcgg gctgtgcgtg ggacaccttc gggtgtgccg 18180 ggagccttac ccccggtcgg ccaacccgcg tacagttcgc ctccctcttc ttggtcgcag 18240 agatggcgaa ctcccaaaca ggtaaggagt cctcatcatg caaaccgctc aagtaattcc 18300 cttccagttc gatgctcgcg aagtccgcac cctgctgatc gatgatcagc cttggttcgt 18360 agcggctgat gtttcttgcg ccttggaata ccgaattgcc ggtgacatga cgcgcaatct 18420 cgacgatgac gagaagggta cgcagattgt gcgtacccct ggcggcgatc aggaaatgct 18480 ggtcatcaac gagtctgggc tgtactcggc gatcctgcgc agccgcaagg ctgaggccaa 18540 gcgcttcaag aagtgggtaa ccgccgaggt acttcctgcg attcgcaagc atggtcgcta 18600 tgaggactcc agcaataaga tggcaaccct ggttggcgaa accatcggca ccgacggctt 18660 ccacatgctc ggctcgctga tcaagggcaa ggtagccgcc ctccccgtcg aagtccgccg 18720 ccgcgccacc gcgaaaatct ggtcacagac ccatgccgca ttcggggttc ggtctgccac 18780 agacatcccc gccaatcagt tggacgcggc ccgcaacttc gtcgccgcct acagcgttca 18840 cgaaggcgaa tggctgccga agcctgaaaa acgctgcggc accatgctca acgaccatca 18900 gctctacgac gtgtacttcg tttgccacca cttccagtac ctgttcgaaa tcttcaagcg 18960 gcacaacctc tactacttct tgaggcagca cggctcgcgc gcaggcgtag agatgatcga 19020 ccacttcaag gatggctaca tgggcgtctg gcagctcagg agggatttcg atggtgagtt 19080 tgatgccgta cagcggcggc tggggctcaa ccggtattct gggctcagca tccgctagtg 19140 attggctcga cgccggctcg agggccggcg ttcgggagga tctgcagcaa ctgctgctcg 19200 gtgatgggca tgtgagctcc agaaacgacg aagcccgcgc agggcgggct ttcgttcgtc 19260 gataggtgtt gtcaggctgg tagctgatcc ggcagaggat acctggcctt gatctcctcg 19320 accttggcca cccaggcgct gtagtccggc tcggtaccgg ccttgatagc gtcgaactcg 19380 gcctcggtct tgagcgggtc actctccagg cggtaggcat ttgcccgcgc gacggctgcg 19440 gcatcgtact cagcctgcca gcgttcttgc gcctgctgtt cagcggtctt taccttgctc 19500 cagtcgatca tcgcggtaac tccacaggtc catcggcatc gatcagcaac ggttcaggaa 19560 tgcgagcggc ggcacttgca tcatcagcca gcgggaaccg caggctcagt tccagccggt 19620 cggcacgtcg cactgcggga ccagcgaacc actctgatcc aatcgcctcg gccggcagtt 19680 gt; cagccctgct cagcgatagg cgttcgccgc tgcctggcag cggatagtac ggtgacaatg 19800 tgatgatcat cagtaccatc tcccaaacgc gatgtatccg ggcataacct cggctctatc 19860 aacaaatccg tgagaaatca gcgtcacaac agaagccgac ggagggttca tcgaaagcca 19920 tgcacgagct gttgcgccct ctctaaacgc cggaaccggt gaaacagatg gcgcagcaga 19980 aaacgcagca ggaaaataga gcgcagcaac gccccccgac tgaaacccac ccccggtcgc 20040 aacgctgcac accagagcgg tactgctaac gccagcgcat atctgagttc cgtccgcaaa 20100 ccgcacgaac tctccgttcg cgttgctccc gcgctggatc accgcaccgg tgggtacgcc 20160 gctcgcctgc gaaaccgtgc cgagaatact gtctcgagag tacagcgcgc ccgaactacc 20220 gagcgcttcg cggacagccg cactgccgag gccgagatcc ccccgcgctg ccgccgcatt 20280 tgcagagagc gcccagggct taatccccgc cagggttgcc ccccactggc tggcgatcag 20340 gttgaatcga tccgacaggt ccttgtcgta gcccaggatc ggcgccaccg cataggcctg 20400 gccgctggcc gtgctgccct ggtagttggg cttgatcgag atgaccgtcg aactggcgac 20460 gtttgtgacc tcgtaccaac gtccatcggg tccgcgaaat gcgtcgccga ctcgggcatt 20520 ggacgagaac tgtgtgccgg taccggtaac ggtcgggcta tttgcggtca ccgccacggt 20580 tccggttgag taccacgcca tagagttctc ctgctatgca atggccagaa gaggccatgg 20640 gaaaggtgtt cgtattgcgt cttgcccagg tccgccgact tgaacagttg ctacgactgt 20700 gtttcgggcc gaagtaacaa acccaatgga gcactctcca gtatcacctt ggggcggttg 20760 cgcctgtaca ttgaaatgac taaccagaaa atacccatca ttcccatgcg gccacggtgc 20820 agaccatgaa tgcagggtgt aatacccaag ataattgcca ttcgtgccgt aataattcag 20880 cagctgggta ccacttatga accgaacaag atccctatta ctgtcaaaca ccactctcga 20940 ctgattgtca aatatttgca tcccccatcc gccagttttc ggcatgaaca ccgcgcatgc 21000 cttccacttc cctcccagta cgacgccgct tgtatcttga aataccttca cgtagaagct 21060 gaaacccgtc cagttcccag ccgaaccagc atgctggaac atcgttatgt gatgcgaccc 21120 attagggcaa aagaaaacaa acggtgggag cgggctctgc accggagatg ggtacgagac 21180 gttgatgatc tgggcattag tggctggata ggttccagac gcaaccagat gcagacaagg 21240 gtggtcctga tcgattatca cctgaccggc attcccaaca aacttcgcac cgaaactcat 21300 gagaacatca ccgcatatag agtgtaattc gctgttacat caccggacca accaaacgta 21360 atagtcgagc cgctaatggt atgcctggga atccaagatc tagaatccgg cgtattgcag 21420 acgacaaaca tgacaccttt agaaccgtcg aacccaggga ccgtaactga aagtccctga 21480 ggaatgttcc ccaagtcccg acgatagacc atcctcaatg agtaattgtt gctgtcaaag 21540 agtattgagc cgccggctga acgtgttctc attccgtaac tcatacatca agattcccga 21600 tctggactcg aagcaccaag tttccgtcat acacttttat tgcctctgcc gtctggcgca 21660 taaaccctcc cgacgttgcg ctgttcattg tgaacgcgcc gcccttatcc aacttccaca 21720 gcggctcgcc gttggcaccg agggcggtcg actgaatcac gttgccgatc ttcgcgttgg 21780 tgatcgagcc gtcctggatc atcgcgttgt tgatgaacat ctggccgccg acgatcgaga 21840 ccggcgccac ggtctgcccg ctggaactgt tgaaccagag gaaccgatca gcctggaacg 21900 ccatggtcgt cacgctcgta ccgctgtcga acccaagctg gaacccggtg gcgtactgct 21960 gcccattggc atgggcctgg atcttcacgc tgtacatcgc cttcacgccc tgatccagtg 22020 acgctacaac gctctgcgtg gtctgaatcg cggccccgtt ggcgctcgtt tgcgcctgga 22080 cggtctctac acgcttcgcc tgcgcctcga tctcattcgc gcgcacgatg acctcggtgg 22140 ctgctcgagc aatggtgtcc caccccttca gtgcatccgc tttctctccg gtagccggct 22200 cccggcgcgc ggctgcttgc agcacgtcca ggctggaggc actggactga acaacaccgt 22260 cgagctcttc aatcgcggcc gcattctcag tcacgcgtaa cgcaagggca tcgaccgatt 22320 cgacgagctc gcccacatca gcccagtaaa cggggttcgg cggcggattg cccgcgggaa 22380 cgtcctggag ggcttgatag aacctgccgt tcaatcgaac gatctggccc ttctggtata 22440 ccgtgcccgc gtcgtagtac tgctccatca actggtcgac gttaccgccg atctgctcga 22500 tattttcgaa gaactgctcg cccagcgcgg actcgacgta ctcctttgtg atcagctcgt 22560 tgtactcgct cgcatccgtc gagctgatgc cgtcgaccca ggccgaccag gggccgacat 22620 tgccggtccg gtcgatcagc cgcccgcgga aggccaagcg agcgccggcc gccagcgagg 22680 tcagcgtgtg ggtatcggtc gggtacgcga acaagcccaa ggcagttgcg ttctgctcgc 22740 tgccgcccgg ggtaaccgac tgctggatct cggtgtaagc ggtgtccgcc gcgccactgg 22800 ccgggaatcc ccactccaga ccgatcttcc acggcccgct ggtggtacgc aggaacgcca 22860 gcgccggcgg cgcgccggtc ttgccgctga gttgggtcag gatcgaactc ttccagaccg 22920 acgtgatgtc gaaggccgac accgcacgca ctcgcgccag atagccacct gcgtagatgc 22980 cggtcacatc gacgctggtt gtgccggcac gcggcaggcg gatccagttg ccgctatcct 23040 tcttccactc gacgtcgtat gccaccgccc cttctacagc aggccaggcg atggtcatcg 23100 tgctgaccgc caacccctga tcgaactggt agtgcgaggt cagcgtgacg ctcgccggcg 23160 gcgccacggt ggtgatcggg ataacgctga tcggccggtt ctccaacttg gcaccagtgt 23220 cgatcgctga gaacttcccg ggctcgtact gcagcgcagt gatctcgaag acaccccgct 23280 ccggctggct gactttcatc acacggtaga gcggcaccgc caggtcgtcg gcatcgaggg 23340 tccagaccaa ttccggtagc ggggtctcgc tgtaggctgt cgtcacggtt accgcgcgcc 23400 cggcaaccga ctgcacggtt cgcgcctcag ccttaccgct gggcaggttc aggagcagcc 23460 ggtcgccagc ctttgcctgg gtatcgcgat ccaaggtgat cactcggcca gcaaccgcag 23520 aaacccgccc cccaatctcc cgtccagcca gcagcgcgtc agccaccgga atcacccatc 23580 ccggcagcgg aatcgccccg tccataccgg tacggaacgt taccgtgcga tcctggctgt 23640 tggttaggat cgcccatttt ccgcgccgct gggcctcact ctcgcgggtg cagccaatgg 23700 ctgccacctc gaccgggttg tcgccgtaac gccgctgcag gcgcttatcg gtggccacag 23760 ccacgtcggt gtcgtagttg ttcgccggat tgtcgtagct gaccaaggca cggctgtagc 23820 gagtgcgctc actggccgag ccgtagctga agcggccgtc gatgacattg gccctggtgt 23880 aggcgaaatc gacgtcggtg gcgcgcggga tatccgcctg gatcttcagt tggccctggg 23940 cccagtacgc cataccacgg tagatagcgg tgaggtcgcg cagcagctcc caggccccgg 24000 cgcggctttg caggttcagg ttgcaggtgt gtcgcggctc ctggccaccc ttcccatccg 24060 gcaccaactg gtcgcagtac tgggaaatcc ggtacatctc ccagcgatcg accatccaag 24120 ccttgatgcg tttacccaca ccgaagcgat cgttggtcac gatgtcgtag gtgtgccaga 24180 ccgggttgtc ggtccaggcc tgtttcatcg tgccgtccca gatgccgagg taggcccggg 24240 tctccggatc gtaattgctc ggcacttgga ccttccgccc gcggcagtcg actgtgacag 24300 ccggaatgtt gctgaactgc tctgcgctga actcgacgta cagcagggcc gtgttcgggt 24360 agcgcagctt cgcgtcgatc acctcggtgt agccggcgat cagcatggtg tcggcgatgc 24420 gt; ccggcaggtc gatccggcgg gaacgctcgt agcgggtggt ggtcttgcca tcgacggcct 24540 cgcgcagcac ctcctgatag gcgccgccgt cggtggccag atctacggca tattcgatcc 24600 ggtacccgcc gatgttgccg ttggtgtcct gctgctggag cgctggccag gcgaagcgca 24660 ggcgcactgc ggaaagctgg gtattgctca gcgagcgcac ccagggcgta tcgctgcgca 24720 actcgacgtt gacgctggtt tcgttctcaa cggcagggat gcccgggatg tagtcctggt 24780 ccaccgcccc cgcgcgccac tcccacttaa cgtttgggaa gttcaggtta ccgctcgggt 24840 ccatcagcgg ggtgttgtcg aggtagatgt cgcgctcgct cggaacgccg gcgaactcgc 24900 cctcgcccac ggcaagcagg atcttggcca tcgcgaccga gcgcaggctg tcgggtgcct 24960 cgaccggctg tttcggtttg ctactgccgc ccttgcggcc ggccaggtgc tggtgaactg 25020 cgcccatgct ttcctccggg catgaaaaag cccgcgcgag gcgggctgga aggttgtaca 25080 gcgtggatga aatgccagtg gcaaccaccc taccggggta gtagcgtcgt gccttcatgc 25140 aagggtttcc cgaccctgag cgtgccggcc cagggatcgg gaggcgccaa tgtcggcgcg 25200 gttaaagacc taggaggtca agatgagcga aaagcccgtt gtgtcaccct tccaactgag 25260 cgttatggcc gcactatcgg tggttggctc aattcttggg tcaacgaaca aaggggccat 25320 cgacaaggtg gttgagcata tcgagaccat caaatccaaa atgccagcag atgcttccct 25380 ccgcgacgga tcttctgagc accacctggc tcttgatgcc ttgatttcag ggctgagggc 25440 tgccagcaag atggatcaga tctaaaggat cggctcaagc ccaagagccg cctccatcct 25500 cgaaagccga cgctcgagca ggtcggcttt tctttccaac tcgtctgtaa gctctttcgg 25560 cagacacagg ccagtgacat caaccggcga gatcgttgcc tccgagacaa gcctttcgaa 25620 ctctgcacta ccaggctgcg gaagctctac gaccacatcc agcttatcga gtttcatcac 25680 actctcccgc ggcatagccg ctcatggttg gttgttacac cttgtcctcg gcgtaaatcg 25740 aagccgagat aatcgccccg ccccaccggc gcttcccgta gcagatcggc accgggttcc 25800 cgctggcggt ggtgtttctg gcgctgccga aggcgtagct gggcaagttc tccggcgccg 25860 cgctctgctt caggccctgt gcttgggggc tgagcatttg gatgacgccg ccggcaacca 25920 tccctatccc tgcaggcagc gcatacgggg ctatgacggg aaaagcgtag gaagcagcga 25980 tcagcacagc cccgactatc gtctgcacca acccgccacg cttccggcca cgcatgaccg 26040 gagcaatgcg aatttcctcg gcgcccccga actgcagctc atcttgggaa atgttccgtt 26100 tcccacggaa tacagcgaac tccatacctc gcaggtggga attggcgagg aagcgctcga 26160 ggcctggaat ctgcacgcac aaggccttga tcgcttccgc agtcgacccg actagcatac 26220 ggtactcccg gccgaactgc cggagcgcgc cgtagagttt gatggtggtc atcggagtgt 26280 ggtgcgctgc gatggtcatg tgtttctcca ggtaataaaa aaccgcccgg aggcggttct 26340 gcactgaaat cgataaacag tgggggtatc tacttctcta tccagtccag ttttccatgc 26400 atatagtgga ctgcactaag ccttcttttc accgagtctg cctttttctt ctccgcgtat 26460 ggtccgacca caattgtcga ttcagcactg gagaatattg gcaactgaag ttcttcgagc 26520 ttcgcaagat gcccatcaaa ctcctctccg ggcttacatg cgatattcac tgtccaccca 26580 tgagttagag gaggcggccc ctcgggagcc ggggttgctt ccacgtccgc gccgcagaat 26640 cgacacttga cggcggcaca cttaatagtt tctgcgcaat acggacatgg ccgagagtca 26700 aaggcaactg caggcgtcgg cgtaagcacc ttcctttttc caagcactac aagcagcacg 26760 cctataagtc agtgcaatgc cggcaatgat tgttctctgt tctctggcag caatgaggcc 26820 tatgttgttc actcgatcgc cagacatggt gccgacagta gtgtccatgg cgagcgcgct 26880 gatgagcatc acgactccaa ccagcagcac gagaattccc agggtgcgca tcccttgctc 26940 tccgcagcga ttttggaaag ggacggactc taccatcacc acgccagcac gagaacccag 27000 cacacagctg gactcaagcg gacaaggagc gttctcgata acgcagtacc agacgcatcc 27060 tgccgtaccg ctgggtctac ctcagtcgtt tcaaggctgg atagaatcac agtgccacca 27120 gcaactcagg tcccgtaatc ttgaacagcc tcgtcaaaac agaccacgag gccgcaatgg 27180 atatctgcca cagctacaag gagcatttta tggccgaaaa gtcgtatcta attgggaagt 27240 gggcaatttt caagagcaga gcctcgacgg aggtgcttgg ttacatcgtg gatggcattg 27300 gacaaacgac ggtgcctgga cagccaccct tcagcattat tgactctgtg ctctttgccc 27360 ctgacggcac caggctcggc tatctggctc cattggaagg aagctgggtg gtgaacctgg 27420 gcgactatga gataggacat gtactgcgtg ccctgccgta agacaccgga aggtattcac 27480 ctgacaatgg agatcacatg atcattagaa gtctcgtcca caatctgcct aaagacccgg 27540 gcagtcccgg ctgggttcta ggctgggcgg ttgtccagag cgcaccttgg agattcatgg 27600 atatttatac gtccaaggaa gcagtggacg ctgaggcgtt actgcacggc gaaggcttcg 27660 gcgtcgaata cggctcgcac gaggtgggca ctgacaactt tgtaggcgga ctcacgccgc 27720 cgagctgatc gcttcgaagg tgatacgccc tggaccagaa accagtcgtg cggtgagccc 27780 aggcttcccg gaatagctac gacaataccc agcgctacct ggactcgtca tgccggcgaa 27840 tctcaatcgg tcgatttcat cctgatcgtc gaggattgcc acgaacgcct cgccgccgca 27900 ccgcacgcca acgcgcaccg taaataggtc atggatggtt agcaagtagc gctgctgcat 27960 actctcctcc cgcggcacag ccgcttcatt tcgcgttccg ataccgcagc gccgatcgct 28020 tagcggccgg tttcagtcaa cccagcacaa ctccgatggc tgctatgatg gatgcaatag 28080 ctacgcctgt ggctaggatg agtgcggcgt tggctagccg cttgccaacg attccagcgt 28140 cctttgcgtt cattttctcc caccctgact gcgcatctct caaccgagca gcctgtccca 28200 cggaagattg ctggacaggt agccaacagc aatcacgaag aaaaccaacc aaagcgccca 28260 aaagcgcggc ggcgacagtt tgtcagtcat gattcgcacc tcgcgaatga tcttgctaaa 28320 atccaagtac gttctcctca tgcctatctc atggggtgga aacaaaaacc cccgaagccg 28380 gccagctctc gggggttttg cttttttggc cggtgaagcc aggatcgccg atttagaagg 28440 cgttgttttt cgctttcaag caagaatctg gtctgattta aggtggtcac caccggaaac 28500 gcgaagcct gcactggagc ctgtcagatc tgtacgcatc cccagctacc ggcatcggaa 28560 gaggcgtagt agcgttatga cctcacaggg ttcccgaccc tgagcaaaag ggcccaggga 28620 ccgggtgcgc caaaatcggc gcgagctact gaccacggag gtcaaatgtc catttctgat 28680 agaaacaccg gcacgccctg gagcgcagag gatgtcgccg aactcaagcg cctcgccaaa 28740 gagaacacgc ctacacgtgt tattggcctg aagcttggga gaacggagga cgccgtctat 28800 accaaggcgt ctgagctcgg cattagtctg aagccgacga accagtctcc ctacaaccgg 28860 cagaagtaga ggccagctcg atagcctctt cgtaggcttg gcgctccctg tccgaccact 28920 tgtggccgtg acttgcgagc gctactgcca gcacgtccag gcatgcggtg attttggtgc 28980 aagaatcgtt ggtgttcata catcctcctg cggcctagcc gctttagcga ttgatttagc 29040 tgacgtgccg cagcaccagt cgcatccggt cgagccacgg cccgccgaac acgatgattt 29100 ctgagggttt cccatacagg tggtgcaaca ggaacggccc ggcgccgaag tgctgcgcat 29160 cctcgccagg tagtgatggg tcgtccgcca ggtagatccc agcgtggttc gggtgcgcgg 29220 tgcgccccac cgccatcacg atcatgtcgc cgcgctgcgg ccggtccacc cggatgaagc 29280 cagcagcctc gaaccgctgt tcgtagaggc ttggaccgtc tgcccgctcc caccagccat 29340 cggcacgctc gaagtgcggg aactcgatgc cccactccct ctggtaccag tcggcgcaga 29400 cctgccagca gtcctgcacc ccatgcacga acgcgcgccc gagcagcggc acctgatcga 29460 cgggctcgat ggtacgcagg tcgccctccg gccagctcag gatgtgccaa gtcaggcccg 29520 aggcgttgca catcgcgaca tctgcggcac tcggtcggct ggtggcatcg gggtggctat 29580 gcaccacggc gacgatctct ccctggtcct ctgcctctgc atacgcctcc ggcgcgatgc 29640 ggaactcctc gccggcgtcg gcagcggtgt tttcgcaggg aacgtatcgc tggctccggc 29700 cagaacggat gatcagtccg cagcactcgc gcggatactc tgccgcagcg tgcttctgca 29760 cggcagacag gatgtgcttg agcatggtca gctcctggcg atgatcgaga cggcagggaa 29820 gccgccgaag ggcagttggt tgccttcacc gaagcgcggg atgcaaccgg tgcccaggca 29880 gccatcacac tcgtcccggg ctgggtcatc ggtggggttg ccgtcgatgt cgaagtacgg 29940 gccggtgtag ccgcagtcgg gcccgcggta cccgcccgtc atcgcccagt ggcacagggt 30000 ggtcatctgc cggccgacct gctcgccgcc aacgtcgcct ggcgaggcca gttcccaggc 30060 cacgtactgg ccgtcctcgc tggttttctg gtccaagtac cagatttcga cgatctcctg 30120 ggagggatca gcgtcgggat tgccgcctgg gaagttcgcc gcgtccagat atttcgcaag 30180 cgtcgtccgg atggtgaggc ggaactggag caggtcctcg aacgccaggc agagcgccgt 30240 aatccggcca ttgacgttgc cggcggtgaa gctcggccgc gccgcagtac catcgctgtt 30300 ggcctcgatg ccctcgatct gcaccggcca ggccgcgtat tcgcggccct gccaccagat 30360 cgatttcgcc ggcaactggt cggcgttggc gccggcggcg gccagttcct gcggactgtg 30420 cgggatagcg tgaccgtgga accggaccac gtcggcgccg aagtcgctgc cgtcaagctc 30480 gaacaacacg acctcgccgc ccggctccag cttctggata tcggtgatca gtgtcatgga 30540 tggaatgcct gttcaaaggt cgcggtcagc cggtagaccc ggccaccgag gttgacgggc 30600 cggtagcccg cacaggtgta gaagcccaag tcgcccaggg gcggcgtcca gagaaatgca 30660 cgcgctccgg tgtggcggtc caggaagtcc atcacggcct tgatggtcgc cgccggcccg 30720 gtgatggaca ccggccagct ctgggacttg ctgttcagac cttcgctcac caactgcttg 30780 tagccgtcac cgaattgcgc ggacctggtg gcgaaggtta tgtcgccctc gccaccgctc 30840 tcggtggccc aagtgaaggt ttcgattgcc atgtgctcta cccgttgatg gcccggccga 30900 tcgcaccgtc acgccgcaga tcacgcgcca ggagttgtcg gtatttctgc tcgacgaacg 30960 tcccgatgtc gcgaccgaac tggtccaggc caggctggct gctggagacg ttggccgaac 31020 catccgaggc aatgttcacc tcgacgttga tctgcgaacc gccgccgccc atagcgcgca 31080 caccgagggc gccggacgag gttctggtca gcggcatcac tgcctctggc cccgcttcgc 31140 ccatcacacc caggcggccg ccgctcatgc cgaacgcggt tggcgtgctg accacgctgt 31200 tggtgaaggc cccgccagtg gcgaacatct gcacgccgcc ggcgaacgca ccaccgttgg 31260 cgaacagccc gctgttgctc accaggttgt cgacacccga ctgcgcggca gcgtttccac 31320 cgccgaagaa gccgccgaag agggacgaaa gggcctgcga ggcagcggcg cgcgttgcaa 31380 tccgcgccat gtccgccagg atgctcttgg cgaagtcgga gaacgacagc ttgccggtcg 31440 tggcgaagtt ggcgattgag tcctccgcgc tgctgaacgc gttggtgagc aggctcttgg 31500 tttggcccgc cacgtcccga gcactttcca gataggtctt gaacgccgat ctggctccca 31560 gcgaccaatc cttctgagcc tcatcgactt gatggaagta gtcgttctgc ttggccagcg 31620 ccttacggtg ataatcgtcc agagcagaga gttccttttc gtactggctc tggctgatac 31680 cgccgttggt ttcgccgcgg ttgcgctgct cctgcagttt ggcgctctgg ctctggtact 31740 cctgctccag cttcaaacgg tcctgaatgc gccggcgctc ttcatcgccc gcaccaaggc 31800 cagcgatctg cagttcgtac ccctgctgca ctgagcgcag gcgcccctca aggtttgcgc 31860 ggtacgcgtc gatcctggcg atttcctcct tcttcctcgc ctcggcctcg agcgccacgt 31920 tcttctgaag ctgcgcgcga acctccgcct ccctagccaa gagagacttt tgatcggcag 31980 tcaggacagc tttcaccttc aggtccgcaa tctgctgctc ccacttcgcc atctcacgct 32040 gcgaagcgga cagtttctcg ctggtaccaa gttgctgctc cagggctccc tgctgctcgc 32100 gcagacgcaa caggtactgg gtagcagcat catcacgaaa ttgagaagac ctggccgcct 32160 tcgggtcctt gaaccgctga ttgatgccag ccaccagctt gtcgaaggtt ccgcctgata 32220 cgctatcacc gacaatattc acacccttga gccagtcggg aagcgcgctc aacttgcctg 32280 ccgagatcat cttctcggcc gcgcggtagc cggcgacgta cctcttggtc agctcatcaa 32340 tggctttcgc tcgcttggcc gccggggaga cgttgcctaa ctggtcgccc agctctttct 32400 caatggcgat gagctgctgg tcagcctcgc ccagctcagc ctccgacttg gcattctgct 32460 cggacaagtc ttttcggacg agcaagaggc tgttctgctc cttcaatgcc tctgtggagc 32520 tgaactgatc ccgaaaggac tgaaatagtg ctccggtagc ggccacgcca ggcaagccag 32580 ttgcggcgcc agttagtgcg ccacgcaaag cattcgacag aaacggagcg ttttgccgtt 32640 gatccaatgt ccgttggagc gtctgtattt gctcattgag ggttggaaac aagtcagcac 32700 ggattgcagc gtaggcatta ccgatcgccg ttttaactgc gtcccatccc tgctcaacac 32760 cagacagaga ctcgcgatac tgtttcagcc tctcctgagc gttacgatgc agatcctcgt 32820 tcagttgatc gacagcctgc tgatggtcgc cttgctcatc gatcgccttg atcgcctgat 32880 attgctcgta actcagcagc cgatactgct cgctaactcg tgccgctgcc ctagtcgcat 32940 catcccccag ctctgacaag gacttcgcca catcctcaat atcccgcccg gtaaattgag 33000 cgattgcgct agtcgtttcc gtgaggctct ggagttggcc ggccccaacc tttccgctgg 33060 ctgccaatgc aatagcagct cgattcgcgc tggccaatga tccggagacc gaagcagcct 33120 gcttagcaac ttgggccaga gccgacccag tcatgcctgc cgcgccattc ccagcaaaga 33180 tagctttgct gaaggaggca gcctttttct ctgcgtcgta gaaagcaaag ccaagcgtgc 33240 cggcagcagc agccaatccg gtaattgggt taatcaagct cagcgcatac ccaccaaccg 33300 cccgcagagc cgggccaatc ccgccaaacg agtctttgat ttgaccgcct tgctgcaaaa 33360 atacctgcat tggcgactga ccagcctgga ggctggtgaa tatgtccgta aactgcgcgg 33420 gaagcccccg catagcggcc tgggtttgcc tggcggtaag gccggtccga cccaactgat 33480 cgttgaacct ggcaaggttc cggctgccgg catcgagacc ggtagattgc tcctgaactg 33540 cggtagcgga cttcttggcc tgttcggcaa tgcgctgctg agactggatg atggcttgcc 33600 cgcgagcgtt gatctcctcc tggtacttgg tccagtcgat ggtcgaggca ttcgccttct 33660 cgagggctgc gctactgctg gtagccgcct tcgcaagcct ctgatggtaa tcactagcct 33720 ctagcgaggc gcgaaccata ttggagatac gtgcggatgc ttgggcagag gtttctccga 33780 ctgaatcaac cgcgctttcc gcactgacgg cggaaccagc caagcgatcc agatcctgag 33840 ccgcctggtc aacgccttgc gagttcaccc gtacgccaag ctcagctatg gtcgtcatgc 33900 ttttctccgg acaataaaaa accgcccggg ggcggttctt cgaacaaact cttagctgag 33960 tctaccgacc tttgagccag taaagatcac catggatatg gtgcgaaatc ccaagcgctc 34020 tcaatactga gttggccgag cgcttgtctg ggaatggccc gactataacc gtcaagcccg 34080 agactgaagc tacaggcagt ttcaactcat caaacttggc catagcacta tcaatatctt 34140 ccgcagactt acacttcact tttacagccc agcctacact cagtccgact ggggctggct 34200 tctccggcac cgcgtcaata tcagccccac agtaacgaca ctttatcgca gcgcacttaa 34260 tcatctctgc acagtacgga catggacgaa gctcatttgc ctgggtttgc atattgggat 34320 tgtttccgct cactgcgccc ccgcgctcac tctctcctgt agaggatgct gcccacacca 34380 aggcggcaac ccacccaaca aaggtccacc cgagaaacag attcagtaca atgatcgccc 34440 ctttattatg atgtcttcta ttctcagcga ttattgcagg tagaaagtag aggattaatc 34500 cacccatcaa aaagataaaa ccgagcagca aagaggaacc gttttccata tccagcctcc 34560 taaaagcccg caatctacca tcaccacgcc agcacgagaa cccaaccgtg tgcggatcta 34620 cgtggctgaa gggggctctc ggagccgaag catcaggcag tctattcctg agctacctgg 34680 tctgaggtgt ccgagtattc ggcgatgcca agggatgcaa tatccatcac acttatcctt 34740 catgaattgt tgacagcgcg gcggcttcca tcatctggat ggcatcgaac agttcggacc 34800 attgcgcctg cggcactccg cgcagccgta agatgtcctg taagacgccg tagtccagtc 34860 cagtgggacc gttcatgcct gttcgccact gggtggacat gtcgcgaaac aacaggaaag 34920 cccgccagtt ctcaggccag atggtcacct cttccaccgg taggtcatca ggcctgagcc 34980 ccagcgcagc aagggcctcc gcatcaggcc ctgttttgta cagggctgcc gccgcgctgg 35040 tcagtttccc aggcgggcct gggtgatctg ctccatgtac accctgacaa ctgtcgggcc 35100 ggcgccgagg tagttctgca gcagccgctg gacgttctcg tcgttgaacg cgtcgtcgag 35160 ctcccatcct gccgcgacgg acataatcgc ctcgcggtca gacagttcgc ccactccctt 35220 caggaatgcg tcgagatcat cctttggcat gtgcttgaag gtgaacttca cctcggcact 35280 gccaccgcca tgcaatggga ttggtactgg agcaatgaaa gtaggcttcg ggtccaggga 35340 aaacttgact ttgctcatac cccctcctta cgccgccagg tatcgaagcg gacgaccaga 35400 caggccaatg ctgatggtgc gggtcatcaa ctgattgcgc tccatggtcg gcgaactggt 35460 gatgctcacg tagccgggat acaggatttg gtcaccactc ggcagtttca gccggatgac 35520 ggtcagtgct ttcgtttccc caagactctc gaccacatcg acatatgcgg cggacggctg 35580 gtcttcgacc gtaatctcca gggaaagcgg gttccggttg gtggggaact gccgatcatc 35640 atcctcttcc aggtagccga cggtcaggta ttgctgctcg ccccccgaag aggaaaagcc 35700 ggtgaccttc gagatctgga cccaggtctc caccggagtc accgagccaa cgccggagtc 35760 cggggtgtag atctcggtgt tggtggtatc cagtccgccc aacgcgaagg tgtcggatgt 35820 gacctctccg atgcggctgg cacggtcaga gattttggcc cagccagagg tgatcaatac 35880 ggcatcgccg acctccaggg agtgaccagt agcactggca atcggcggct ttgcgttggt 35940 aattgccgtg aaagcaacgg cggcccccag tgtggatgca atttccagca cgctgccatt 36000 tggcagcggg aagcgtgcgg ccatgagtat ttcctcttga aagcccgcca ggcggcggat 36060 ggttgtgccc gatcgggcta ttggtcagcc gcgccgcgat aggcgaagct ggttgggacg 36120 atgtaggtgg cgtcatcgaa gatggtcggg ccctgttcta cagggccgga aacaatgcct 36180 tcgaactcgc cgcgcgacag gcgcgagtca acgcgaaaca gagaagtgat ctcatcaaca 36240 agcgattctg caatccctaa tgactggccc gacgggcaga cgatgctgac ctggtagaca 36300 ccccgaaact cgagagcctc gccacccaaa tgaggggtgc tggtcccgct tggaagtaga 36360 taccctcgga ggtatgtctc tccagcatca ggtgtaaaac tggatgcttg aaacgccacg 36420 cggatgggtc ggcctttcgc ccatgagttg agcttttcct cgatagcttg gcgagcaaga 36480 gaatgggaca tacacctctc caaaaacgac gaagcccgct caaggcgggc tttcgttcgt 36540 cggggttggg ttaggcggct tgcggataga tcaggcggag ctggcccggc agcccgaatg 36600 cctgcatgca cctagcttcg aagtctttgc ggtcaatcga actatccgcg atcagcgtga 36660 ccatgcggat ttgctggtcg agccgatcac ggcctccatc ggtcagccac tggtgcatcc 36720 tttcgctttc accgcggcga gcctttagct cggcatgcac ctccttcggc aggatggcgg 36780 cgtaaatcca gcggtcggtg atctggccat agatagccgg cgttcccttg gcatgacctt 36840 cgaaaacggt gccggtgatc ctggccagag cacggtagta gtcatcgccg aagcgcttct 36900 cccatggagc aggagccgtc agcaggatca tacccatcac gctgtccagg ccggcttgat 36960 tacgggcgtc gcggaaagcc ttcaccagcc ggagcttgag gtcgaccacc aggtcgctat 37020 tccgggaaag gctcaggaga aagtacgcct gatcttcatt cagcaatgcg aaacgctcag 37080 ccctgccgcc gccttgggcc cgccgaccaa cttccttttg aaacggcagt tggccaagtt 37140 cctcaaactt ccgctgatag cgcgtgacaa gggcaaagct gtgcttgtgc ttaaccccta 37200 gttgctcggc aatcacgcga ctatcgacgc gcgcctcgcc ggcggagtga acaagctgaa 37260 taacatcggt catggatata gctccttccg cctggaatag gtaagcaggc aggggcgtag 37320 gcggagcgga ccgacccttt tcggtagcga acctagcctg cttatttgat tggtctggtg 37380 gccgagtaga gacgcagcgg ggcggacgga tgagcggaca tccgccgttc ggctgtacgg 37440 gcctagctgc gtgttgagcg cccttgcggg gcggattgaa cagggttcag ctacacgcgg 37500 cccgccctga cggcggcctc cacaatctgc tggaattcgg cgatggtcac ccggaccatg 37560 ccagccggct cctggctgga gtgcccgtac tccagcggta ccgcatacgg caggttgttc 37620 accaggtagg cggtatctcc gagcttcagc ggctggaccc cagcggtcac tgcagaaatt 37680 gccttgctgc cagtcgggtc gacgtcatca atctccccct gtgcggccgt gccaatgctg 37740 aactgccagt tggcccgaaa gcgcccgcca acatacccgc gtccggccac catcccgttg 37800 acgtcgaagt tctggtcacg ctccgccttg gtcagcggct ttgcgtgctt cacgcctcga 37860 cgcagattcc cgttcctggt gaagttgctc ggattcaggt tgatcagggt gttgcgaatc 37920 gcgacgttct cgtcgtagcg gtccgccgca gcactcgctc gctggcggta ggcgacgttc 37980 gcggcccacc gctccgggtc accgactgga gatttctcga tcaccttgac cgacaggtcc 38040 agcatgatcc gctggtagat cgcatcgccg gcagccaagg cttggtcgcg gaactcagca 38100 actgccgcag aaaaacttcc ttgccggcca gaataccgct gccgcatatg cgagcctctg 38160 gccacagcta tttcctcatc tggatggtcc aggtaacgct ggcagggtct tccgagacat 38220 tcagagtgcg gtagtcattg atgaggtccc caaccatggg cgtctcggaa agctctgcct 38280 gtagaacgag cagtttggta tcgaaggtct taatcagaga tccatcaatt tcgctcgcct 38340 tgtatctgcc aaatacaccg cgaccggaat aggtaatggt cgtctcagaa ggcccaccgg 38400 tttcaggatc gtactcaccc tgaaccttgc ggacgccagt gaaaggctta actgcgtcgg 38460 caaggtcggt gtcgaacgcg gcagcaatgt ccgcatgaat ctcgtctcga aggcccatga 38520 cctaccctct ggatagcttg aactggctc tacctccgcc agaacccgac agccaggggg 38580 ccaggagcgc catggctagc gactctccgg cggtgaatgt ctgagccccc tctcggtaag 38640 tcttgctgct cgataccgtg tcggcactga cgctctttgt ttggacgcca gtctctcggc 38700 ttccatacac cagccctttg gctgcatctc gcgccacctc tgctccagca agcttccact 38760 cttccggaat ggagttcagc tcagggagct ttcgattggt gagccagacg ttggcgatca 38820 acaccgcgcg ctccttcttt tcaggagagg cccaatcgga gcctagagca gcatcaacgt 38880 ctgcaacgtc gatgtaggtc ttcattcgga agcctcccgc aacgcttttc tcaccctctc 38940 aggcccggcg ttacggtgga cgctgacacc ccgcgccttg gccagtgcgt gcagttgttc 39000 ggcgtccatg ccgtccaagt cgtcgtcaat ggcgggctgt tcctgccccc ttgctgcatc 39060 gctagccagc ggagcaaaag cagcatcaac gattcgatac cccatcgccc gcaactcagc 39120 cttgcgctcc ggcgtgatgg gatgcggttc gtatacgatc gtcatttcga ttactccgga 39180 gtgaagacag cagtcaccac gttcgccgca acacttaagg tcaccgttcc gcccgcgact 39240 gagattgttt gaccgttggc taccacagcc gcagtcgctg ccaaacggat accagcgaga 39300 gccccgcttg caacatcagc ggtaccggaa gctagcgcca tcgagccgct ggcaggcagc 39360 actgaaacag tcgcgtcatt gctaaccaca acctggcctt cacccactgc cggggctgga 39420 ggattgtccg ggtcgaacac cggaaggcct gcatatgcct gaggaattgc acctgctgcg 39480 tagtcgccag gaaccacata gtcaggctca accgccccat tgtggacagt tacgctatag 39540 gttggcgggg tgagagcgtt gagttgctca actacggact tctctgcctc ggtcagcgca 39600 ggtcctgccg tgaaaaacaa aatccgctga gtcatctgga cctcctattg cgcggacggc 39660 ttttacaccg tccgcgccga tggttaggcc tggccgacag ccagaacgcc agcggtatgc 39720 ttcacactgg ttgcaacctt gtcccagttg gctccggtgg acagagcggc atcatccggg 39780 gatgccccac cattagctac atcccaggca tacccgcgca gccctacgcc gaagctgtag 39840 tcgatctgca gagtggtctc gatgcgctct ttgccgttgc tggtctcgat gttcgagatc 39900 aggtctcggg catcgtggac agttgcggcg ccttgggtca gcgagagtac gcgacgcttg 39960 gcaggagcag ccggatcggt cactgctggg gtgtagagcg ccggggcatc ggtcaccacg 40020 atcaagcgac cgaggatatc caccacgcgc acgccgttgg attggaacag ttgctgagcg 40080 ttggtcagat tctggccaat gaaggtgtgg aactgggcac catccataac ttgcgcgatg 40140 agctggctag agtggtcgcc gaacagcgcg tggctatcgt tgaccgcaat gtagtccact 40200 ttcttggcat cggacacgtc gacagtggta gcggcgcctt ggttgctgat ggcggctacc 40260 agggcggcaa cggctgtgtt caactgatcc tgcagaagag actcggcgaa gtagcgggag 40320 gcgacttcga caccttcagc agtcggcttg cgcagccagg tcatttggga tggttcgtat 40380 cgaaccgggc cgaagccacc agccaccttg acggtattgt gcttcagctg ggtcagatca 40440 accggagtta ctgcgtcatt cgagccgtag cggttcacgc gacggcgagc ccctgccagg 40500 cctgcataga aactggtttg caggaagtcg ccgtcgaagc cgtcagtggt cagaaggatc 40560 gcgccaccgg acgccgcatt gaatcgctca accatctggc tcagcgtctc gacggtggcc 40620 ggcatgaaat aggtgttgaa cacctccata tcggaaagtg ccatggtgtt tcctctctag 40680 gtgcgcccgg atgggctgga tttagtgaag tgtcagggcg tccgccctgg agcgccgtac 40740 cccatccggg atgacagcta gactccgatc aggccttggc cagatcaggg aattgcgact 40800 tgatagcggc gagccggtct tcgcgattgc ctccgaagtt gcctttcagc ccaccgccgt 40860 ttgccggcgt gccgccgtta ggggcgccgc ttccagactg gttggctcct ttcagaatct 40920 ggtctttgta ggggtactga tcgaccaagg tttcgagcgc ttcgtcaaag tcagccacct 40980 ctcccgggcg ggatcggctg aaaatcttgt ttcccgcctg gtcgtaggcc actaccttgc 41040 cttcttcgat ccggaaggcc tgaccgaatc gggcctgcac cagatcgccc gggatagcga 41100 atttgtcggc gatgaactta gagcggctaa agctgccacc aatcaactcg ttgtgcagtt 41160 gcccctggag cttctccaga tcaccctgaa gctgcttctc tcgctcagca gaggctttcg 41220 ctgcggcctg aacctgctct tcggcagcgc gcttggcggc cgacttgatc tcttcgactt 41280 tgccagccgt aacgagatcg ccgtccttga ggttcttcac tgtttccagc gccctgactg 41340 cagcttccgg atcgtcgatg ccttcgaaca gcttggcgcg ggcctcagcc gcctcttttg 41400 cctcacgatg gccttgagcc tcacgattca gggccgaaat ctttgccacc gccgctgcgg 41460 catcaaacgg agcctccttg ccatcttcgt gcacgtagat gggcttcccg tcttgcagaa 41520 ctgcatttcc gttttcgtcg agcttgagtt tcatggtttc tcctgggcat ccgcccggtt 41580 tctacggcca tccggccacg cgccctgttc atccgaacgt cgggcatgaa aaagcccgcg 41640 caatggcggg cttggtgttg aagtcttcgt tcagtcgggc gcatagagtg ccttgagttg 41700 ggctaggctc agcgggttgc cccgctggtc caacaggtca ctcaaggtga tgacgcctcg 41760 gcgccagagg tcggcgcggc cgggccccag cttctcgtcc tggaaggcct tcgacttacc 41820 cttgagccat gtctcgaagt tcagactggc cggcacctgg ccgtccatcg acgcccgggt 41880 gctcttcacc tcgtcgacgt cgatacctag ctcacgcatc gttttgagcc aaggcagagt 41940 ggtactgcga cacccccagt gccgcgggca accttgcttg tacggcaacg agtgccccac 42000 aggcatgaac tgcagatccc aggtcttctg gtcgtagacc atgcagattt cagtggtgtg 42060 cgagtccagg gtgctgagct ggcgatagcc tttcaccggt ccattttcgc cagaattggc 42120 cttgtagacc tccatcctgg cgccattggc caccgcttgg gcgctgttgt ggaccaaggt 42180 ccgagccgcg cgcttgctga catccatgaa gcccttcacc ggcggttggt cgccccgagc 42240 ccggcggcca acgatctggg tgaccatctg ttccgtggtc tcgccgttca cgaagccatt 42300 gcgcaccaca ccggcgaacc gaaacgacac atccgcagcc tgcttgagcc accattgctt 42360 ggtaggcgcg ccctcgatga gcgtattcgc aaccacggcg ctgagtcggt tcttgccgac 42420 gccgagcatg attggccggc tcaccaggct gttgactgag ctcgacgcga agcctccttc 42480 gatgaccgcg agttgccgaa gattggcatc atgcgccgca gcgatctcgg tgtactgcgc 42540 cttgattgcc ttggccgcct cgtcgaggat cgcgttgacc tccttgacgt tcttcaacgg 42600 cagccgacgg ccctgtagga gcttgataag ctcctctgcc aactcggtga tcttctcctc 42660 aacttccttc gacatacccg ccgtggtcct gatcaagtcg ataccatggt cggtatacag 42720 ctccgccagc aagatttcca agcgagtcat atcgtgggag cctggttaag aatgcgctct 42780 tgctcgtcct cccacttcaa cgagtcgctg atgacgccgc ggcgcttcac ctcgttgaag 42840 agagtttcct gacttaggaa gttggagtct gccatctgct tgagcactgg caggctcacc 42900 tcgggcgcgt agtcggtgtc gtagttgccc tcaaccgtcg caaagccacc gctctcttga 42960 ttcgtccagt ctgcgaagag ttgcagcatt tggtctattg cgtcctcaaa cgcattaccc 43020 atggtttcga gggcgctaat cttctccgca gcctcttcgt tggcttgtgc agcggttttt 43080 accgcctggg catcgcgatg aaggagccta gcgccggcaa tgcgcatctc ctccagcagg 43140 tcctgcaagt cctgcctgcc ggcctccata gccctgccgc catgctcaac gaacttaagg 43200 tcggcaccgt caccgttaat acgcgttgcc gaggatgttc ctaccgtcat ttcccatgga 43260 atcggcgatc cgtctggccc gaccgcatcc ccagcattaa tcgccaccag aataggtact 43320 ctcgccacgt gcaggagatt gcgctggtcg ctttggctct gccaatgagt aacattcaga 43380 tgtgccagct caatcagagg aggcctggcg gtcatgatcc cggtctggcc ggtgtagaac 43440 gtcacaagcg ggattttgtt gagagtggtt ttgccttcat catgcaacgc ccaaccactg 43500 ccatcgcgtc gataggtagc ccagcggttg atctcaagaa cgcgaacctg ttggacattc 43560 ttggatccga actccccatc ttcttcctca atctcctcca tgtaccgaaa ttgggtaagg 43620 acagggcggc cgcgctcgac tcgataccga tagcccagaa cttgctgcgg tcggattaga 43680 acggcataag gacgaatccc ctcttcccgc tcctgggcga tagttttcac gccatccgac 43740 ggcgggtagt caactaggca gtggcacagt ccgtagccaa gcccagccct aaaccactct 43800 ccggcaaaca catccaggtt attccccatg aggtcgatgt cgtcattaca ccaaccagcg 43860 atatcaccgg ggacttcatc tcccagtgtg atcgggcgcg ccagaacgcg accggccagg 43920 ttcttgactg tctcagagaa cgctggaagc agagtcgagc gctgcagtct ctcctggtag 43980 ctttcctttt cctcttttgg ccacttcggc aggtgcttct ctcctgcctt tcgcatcgca 44040 ttagtaccgc ccaggaggtc tgaaaccagc tcccagtctc ggcgcatcct ctcaacggca 44100 tcgagaacga tgtcagggct gtcgttgcta gacatggggt tacatcctga gtggtgtcga 44160 ttggactggg cgagcgttta tcggataccg cttggcgatg aagtagccgg cggcgtcgtt 44220 catgtggtcg taaccattct tcgggttctt gtctggctcg cccttgtcgt tgtaggtctg 44280 ccgttccagg cacagggtca gttgcggaca ctggtcgatg ttgaccttga gtcggcgctc 44340 gccgtatgtg ttcagcagca tggcgttgac cgagttcacc cggtctttga cgctcgggtt 44400 ctgggtgtcc acgatcaccg tgaatccagc tttgcgcagc agggacaggt ccgactcgct 44460 cgcgttcttg ctactggtgt tctggccgct ggcatcggga tagacagcta tgccgtggcc 44520 cgggaatcgc gccttgattc tctctatcat ctcaggcgta tcgcgcaccg agtgaaactc 44580 atccagggcc aggggcaagc cattgcgcac gacgtagacc accgcagcca tcttcatgac 44640 gttgaggcc atgccgatgt gcagagcctc tcccggcttg attcgctcgc ttgtgctgtt 44700 ctcgctacgg ctaaaggtgt agtagacaac cccggagtag ttctcgaagc tggcttcata 44760 ctcctggcgg aacgtgcgcg gatccatctt cctgcgggcc gcttccaact cctcagccgg 44820 gacgttgcca ccctgcagcg atgtatagag ccagctcttg tggtctggct cgccgccgac 44880 ctgaccgtcg cggtaggtgt cgaagcagtg gttgaagcct tttggggtgc caattcgcag 44940 cgcgtggccg cccttgcact tgccgatacc tggcacgacg tactcgcacg tagacagcat 45000 cgggcgcagc acttcttccc aggccgccca tttgcagtcg gcccattcat ccacaagaac 45060 gaagaacagg ccagagccgc gcaggtcgtc gtagttctcc aggcccacac agcgaatcag 45120 gtgaccactc ttgagcgtga tcagcatgtc cgactcgttc ggcttgcact cccgccactc 45180 tcgcgggatg gcttgcttta gccggcgcca gaacactcga cgagcctgct tctgcgtcgg 45240 agccgcgtac cagatctcgt cctcgatgct cacgccccac tcagcagcca acctggccgc 45300 gcggcgcatc tctgccttgc cgaggaacgt cttgccaaac cgccgaccac agaccgcatc 45360 cctgaagcgg gcattacgct ggaagcccca gacgtagatg tttgcctgct tcggcgtcag 45420 ttgaacgggc gcatcatagg tacggggcag ccgggacatc ttcgtcaggt ctcaggatgt 45480 actcagtttt cgcctgctgg tggtccggct gggtactcag ggatcggtca ggctcagcct 45540 ttcggttcac atagacgtca ccgcactcct tggccgcctg ttccaacaac tgggcggtca 45600 gcgctaggtt cctcatggac tcggcctttt cggccatccg ccccagcgtt cgaagccgga 45660 acgcccggtt ggcgataggg atctcggacg tctcttcgcg aaagcgcttg cgggtgtcct 45720 cgaacagagt ccgccagcgc ttggccaggt ctcggcctgc gctcttggtc ggatcatgcg 45780 actcgcactg ttggcggctc acctctatac cgaattcttc tcggacagat gccgccacct 45840 gtgcgggggt atcgaaacag gccagggcct gcacgatgaa ggctttcacc tcattgttca 45900 ggactgccat atgggctcac tccgtcttag ctctgtcatg gatcaggccg acttgagcag 45960 acaggttccg caggccctcg cgatgttgat ctttgccact tctggcggct tgctggcagc 46020 gtcgatcatc tcttgcactg cctcactggc gccgtagcgg cgcaccaccc cgacgaactc 46080 attcacgtca tgcccgcgca agtagaggct cggcatcccg tccgagctga attttggcgc 46140 gccgaactcg tctgtcttct gggctatgtg aaatagttca tgctccaaaa gcgagcaaaa 46200 ctccacgtcc gaacactgcg agcagtagtc agccgccagg gtgatgagga agtccggctc 46260 ttcaccaaac cattcacgca tctgctgctc ttgccgggcc ttctgccaac ctccagcgcg 46320 gaacatgacc tgctcggcct ggcccaggac ataacggcct tgcttggtga atccagagga 46380 tgcccagagg acgcggatgt tcgcgtcgat caggtgggca tgctcagggt tatggatgct 46440 gccggtgtca gcaaggatct cgcgctgaac ccaatcccac acgccgatag ctgggcgcag 46500 gataagccac agtgattcga gcatctcggc cggcggcatt ggtctactca tggatcgcct 46560 gtatcttgaa atagcggcgg cttaccgcta ctgatggatt tccaatcaat gcgaggaaac 46620 gcaatgtcga aagctattga cgcaatactg gagagctacc aacggagcat cagcgatggc 46680 gagaagcgtg ccattgccgt tgccgcagca ctgcaaatta ttgaggccaa ggtcagcaat 46740 gcacccacca acaatgcagt ggttgagaat gagttcaaca acttgaacaa atatgccgat 46800 cagatcctgg ccgccctcaa gggcgaatga gccaacagtg ccgcacttag ctgcggcaca 46860 cccaaacccc gacgtggagc caacatggac attgatcatc aggaagcccg ggcgattgct 46920 gacgagcttc ggcgctggca cgacgaagct cgcagcttga ttgacgacgc cgctgataaa 46980 tccaggcttt cgcctactgg tatcgactca ctcaaaaccc ggctctctat tctcaagaac 47040 gagatcaagg aagcggcaaa gcacgagacc ctctcaaggc gaaaaaccgc aaagactgaa 47100 ctggagcagt gcttcttcgg tccggcagtc agaagcacat cggccaattt ccgcttgcgc 47160 actgacacaa gccccaaaag cgagctttgg gcgcgtggtc tgcatgaggt ggagtttgag 47220 ctctcttact ctatcgacgg cctagagcgt ttcgtagctg aaaactcgta gcgcttcgcg 47280 ccacaaaacg gtgcatttcg aatttgtggc gcgttacccc ggctggaaca catgatcgcg 47340 ccggacgacc ggatatcgga gccatcacga tttcccagtt aacacgtaac gacggattgc 47400 ttgaaatcct gggcgatgcc gatgggtggg cactgataag cggggtattt cggagttcgc 47460 ttctcgaaga cgagcttcag atgatccttg atctgcaacc actgcatttc gtttggcaga 47520 gccccgttta attcgacgaa accttgcagc cagtatgtga attgttctgg ggtcatcagc 47580 tgcgccttcc cttaattgcc tcaagatacg catcgtatga gatgcgcgac tccatctctt 47640 cgccgcagag cctcacccgc ttgttaacga gtgcgaacgt gaccgtgacg gttggaacag 47700 ggccgtcgtt gctgaccgtc agcgaaagct ggccagggag cggcttcccg ttgctgtcac 47760 acaaaatcag gaatgtgccg gtgttcttca gtagaagcgg agcatccatc agtacaccct 47820 cagaatgtgg gccaggttcc cccgcgcacg acagacaagg ccgagcagga tcgccagtac 47880 cagggtcagc caaggggaga caggattcag cctgtagccg tgtagcgcat cgagcatcac 47940 gctcagggcg aaacacccac taccaacgca cagcaggtag gcgagccagg aaacgccccg 48000 gcgatacctc gcaccttgcc ggcggtatgt cgccaaccgc atgcagatgg cgccgcaaat 48060 catcgcggct accagagtcc aagggtcaac cattacgacc tccaaagcgg tccgctatga 48120 agcggagcca accaggcgtc ttccccccct gcacccactc cagcaagctg gtgcccactg 48180 cgacgcagaa caatgcccca ccaaaggcga ccaggcccga tgtccttgcc cactcccgcc 48240 caatgacttc gccggcgacg tagtagccaa cgatccagga cgcagcgaag taaccaaggc 48300 gagcccaggc cgagatgtcc ttggcataca ccacgaagaa gatagcccca gcaaaagccc 48360 cgatcactgc attggcatca atgccaggga tcaacgcaga cgcaccaata ccgaccaagc 48420 cggcgactgc taccgcacca ctcggctcgg ccatattcac gtactccaga tgcagaaaag 48480 cccaggtcgt tgcctgggcc ttgtagtgtg gctctcacga agaaaagacc cgctcatggg 48540 cgggtatggc cccgtgctat cctcgtgatt cctacaccac gaaacaggac ggacccatgg 48600 caaacttcat tgtcacgttt caaatcaagg ctgatgacac ctaccagtct cggtatagtt 48660 ccttcaagaa gaagatcaat gagttaacca gctacaaaca ctgggatgaa acgacttctt 48720 tctactgctt cgaactggac tacacggcgc aaaggctttg ctctgagctg tacaccggca 48780 gcgagttcaa cgcaaccaaa gacataatgg tggtcatcga tgtatccaat cgagaaaagg 48840 ccacgaaagg tccgatccag tatgctgcac tgctcgacgc ctacctcggc ttctagttag 48900 gtccgcccag caccgaggat ctgcgactcg atctcagcta cacgatgctc atattgggaa 48960 agtgtctctc ggttaagtcg cagatcttca gccagcctac gttcttgggc agccgccaaa 49020 gcatacaacc cttcaacctc cgccagcttt gcttcttgag caatgacaga ctccacagct 49080 tgccggtatt cgcttttcat gtacgttctc cgcgcgcagg gttaagcctc tcagcacttg 49140 agtatgaggg cctggcgtcg agtgggatgg attgagtttg gagcggctcg cgggacttga 49200 acccgcaaca tccgacttgg aaggacagcg ctctgccagt tgagctagag ccgcagaata 49260 ggtgccggac tagccggcgt cacgcccgca gagcaaggag ccggggcttt cgccttgatc 49320 accagtggtg aaccttgctt tcttctgccg catgcgtgat ttggagtggc cggtgctgat 49380 ctccggcttc tggctctctg tgttcgttgc tgcgcctagg cgtctgtgtc accacgggct 49440 tgccataaac cctcgattcg cagcatcagc accgctgcat tcactccgtg ccggtcttcc 49500 accggctccc acttcacttt aacgcctgcg tgtccaaggc gatcccggag tattaggtcg 49560 cggtagggcc gggcacccac ctttgaccat cctcggccgc gtagtcgcaa cccagaagga 49620 ttcagatcag aactactacc gctccaacca ggagcagcag gaccagcgcg ccaccgccga 49680 tacccttgag cagccaaaca tctttcgatt cagcagacat tgcagaactc cgtagacggc 49740 tggaaacgaa aaagccccgg cagatgccag ggcttcggtg gtgactttcg ccagaggcga 49800 atttgtcacg atggagataa gtgtgcctca gccgcacatt tgtcgtcaag cagcattttt 49860 catcattttt atcgccgaag agacaggcac aagcgcggcc ttgtcgagat cgttgcaggc 49920 atcgaaacag gcctggataa agccgtccca ttccctatcc cagtttcttg ggtcaagttc 49980 aatgccatgc atacggtcaa gccaggcgcg gaacgactca gggcttgggc agggatcaac 50040 gccttcgctc tggccgccct ggtgcatgcg acggtaccgg aacaagactc ccgcagcgac 50100 atagcgcgcc ttctcgaatt tcttcgtgta catccttggg ccggtttcgt aagcgaccct 50160 gaacacgatc tcttccgcag cctccttgtc gtcttcgcca gccatagggc tgtacatgtg 50220 attgccgaac accttcagat gcgccgggag ggtatcgatc gccttttgaa tcacgccggc 50280 gagtgcctga tgaacagccc gaggagtgct gatgtcgcgc tcagtcttgg tctggtggat 50340 tcctggcaca aaggtgtatt ggctgtagga gacagcctcc ccttcatcgt cgatctcggt 50400 gatgcgtcga cggacatatc cgccagcctc gacaattcca agagcagctc gctccgccgc 50460 ctcggccatg ccgctgttcc aaggggtata gaacgcatcg tgccaggcaa tgcgcgcgct 50520 gtttagattc atgccgtagc cctcttcagc tcgcgcagct tggcgcggta ctcggcggtg 50580 atcgccttca gttcgtcgtt ggtgtacttg cggggacggt gatcggcttc cagagcctct 50640 acagcttcca ggccgatgcg ttcgatcaag ccctcacgga agccctggga aacggtaagc 50700 cccttcctgg cgtacttgct ggagccggcg ttacaggcct tgcattgaag ccatatgttg 50760 gatggctcca ggcggtgctc gggccttgcc cccttgccga gaaaatgccc tgcgtcgaat 50820 gcacctccag tcttccagcc ttgttcggct agtacctcgg cctgagactt gccgcagctt 50880 atgcagccgc ttccgatgga cagttcgtag gtgcgccggt agtcccgaac ggctttctct 50940 gcatctttga tgtggtcgct gtgcgtcttc agcctctcct tccgaacctt gatctcccgc 51000 cgctcgcggt ctgcgattgc cttccgcgcc ggctttgagt gcttgtcctt gatggccagg 51060 gcgcaggctg gcgagcagac cttttgcgtg ctgctgaagc gaggggtgaa ctcctggctg 51120 catgcagggt tctggcattt cttcggtttg ggctggctgg cggataggct cattgaggct 51180 cccccgaaac caaggctttc cagcagtcgg tgaaagcttt gctgaagtcg ccgtagagcc 51240 tggacgattc ctgccggcag gcccgaaccc cttcgccgac tgcctcgcat acagccacca 51300 caagcggcac ccagccaaag gcgatcatga tcaccaggac aatgagcgct cttggccgaa 51360 caggaactct ccgcatggcg cggaagaaca agctgcggct catagctctt ctcccgcgaa 51420 gtagccaagc catagggtgg ccgtcccaac cattgagaca atccatgggc tgatgggcgc 51480 agaggtctgc gtgtagatga tgagtgcgat gaccagaagc tggcccacca gaatttttgc 51540 aatctgtcgc ctgctcatgc ctccacctcc ttcgccttct gctgctcggg ctggaagtcg 51600 ccgcggaggg gcatgagata ccgttcaggg atgtagagcc gatcaccttc atggagcacc 51660 caccaggctg cccgattcac cagaaaggtc tggccgtctt cgacaaatag atcacccggg 51720 gaaagtcgag atatcaactc gactaccact ccagcgctga tgcagtttgg gatttcttgc 51780 agatttagag cgaggtcgcc cgccttgaac ttgctcatgc ggcctcctgt atcatcagcg 51840 gccacccttg ctcagcggcc catgcttcga tcttggtcat gtaaatgccg aactcgtcga 51900 cgctcagctt cgtcgtactg attccgcgca gttcggtaga gccgtcaggc agcgcaacat 51960 cctcgcagcc gataaaccag cgcttgaact gctcgtgcca gacctgatcg tcgaactgtc 52020 ggttgtcgac ccaggcaacc gatgcaagct cgcgtagaag ggaccagtag cgcttgttct 52080 gctcgatgga gcgcttcgac ttgagcgggc gcaggaccag ttcgtagccg ccctgagcgt 52140 cacgcatgag cccctggatg aggttccaag cggcgaggaa ggcaggacga atacctgcgg 52200 cccttgaat gcggaatgtg cggtcagcca ttgcgcgccc tccgctcagc ccgttcagcg 52260 cagtcccggc atttacgaac accagggacg atcgagcgcc gcgctaccgg gatttcctcg 52320 ccgcagtctt cacactcgtg caggctctcg ccgacgtact tgactcggga gtacaggcgc 52380 tcagcgagtt cacgctcggc gtagtcgttg gcgatatcgg cgatgtcagc caagggacac 52440 ctccatgcgc gcagcttctt tgcgcttgcg aatcagctcg gaaacgtcgt tggggtagtc 52500 gatctcggtt gccccgcatt caatcgcttt cgccttcttg ctgaggcaga tgtcgaagtg 52560 gcttttgatg gtcccaggga actggtgcca gcggcgctgt acgccgatct tgtcggccat 52620 ggtcagcagt tcggcatcgc tatccgcgaa catgtggcac atcttcatgc ggccataggt 52680 tgcgttcatg ttgtcgacgt aaacagccat cactcgaccc tcccttccga ccaaatgctc 52740 ttcacgacat caaccgggtc gcagtcttcc atcaagatca tcgtgaagcg cttggcgcct 52800 acgattacgg tccaagagcg tttcatttgg aggccctcat ctcttctgga tcggactctg 52860 cgcactccat aacggccggg aagtaacggt tgcgccacca agcgatgcct cgatctgaca 52920 tagacagctc gcgatcaacc gagcaacgat catcgttggt tcgcctatgg gtaagccgga 52980 ggtagtcctc cgcctcactc ctgcccatca tttcgagcag gacctcatca acgacttcgc 53040 tagctgggcg caggcaatcc agaatgtctt cacggaccga tagaattgcc ttgagccatg 53100 cgccctcccc cgcggctgta agaaatatct gacctaacca atcaagcgac atttccaccc 53160 actcctcgtt gcgcggaacc agcaggtaac aattcatgaa cccgcgcgtg tcgctctgtg 53220 gcctggaaac cagaaatacc actgggcgcc ccgtggactt acgcgtctga tctgctttgg 53280 ccacctcaat ctcggtcggt cgcgtgcctt tgacctcgag atagatatct gccgctggaa 53340 ggtagaaatc cggcaagtac ttgcatccct cgacttgaat aagatgcggc tcgtagagat 53400 agaagatgtc cgccgcgtcc atgagtcgag cccacatcaa ctcggtgtag gagcgcagtt 53460 tgtatccctg gtgctgatag atagtccgcc gcctttcatc acctttcatc accagtcctc 53520 cttctgctcg ggctgttcgc ggtagtggct tgcaagcggg acgaatcggg atttgctccc 53580 ctggaaggag gtgaatacgc tgccgatctc tccgtcccgg ttcttccgga tcaggatttc 53640 gccgataccc ttcctgtcgc tgttcgggaa atagacttca tcgcggtaca cgaacatgac 53700 gatgtcggcg tcttgctcaa tggcgccgga ctcgcgcagg tcgctgagga ccggacgctt 53760 gtcggggcga gactcgcacc ctcggtttag ctggcagagg ggaagcacag gacacccaat 53820 ctcccttgcc aacagcttca tctgacgcga catggtggtt acgtcatcta cacgcccctt 53880 gccatcgccc tctacgagtc ctaggtagtc gatgacgatc agccccaggt cgcccatgcg 53940 atgcttctgt cggcgggcga tggaccgtat gcgcggcatc gtcattacag gcacgtcgct 54000 cacggcgatc tttgcgtccc ggagcttgag gactgccgcg ttgagctcgg tgtaatcttt 54060 gtgagtgcag gaaccatctt tcaggttttg cagagagatg cctccgacag ccgcgatcag 54120 gcgatccatc aattgagcct ttgtcatctc aaggctgacc accagaacy gccttccctg 54180 cttgatggcc acgtctgctg cgatattcat tgccagggtg gttttaccca ttgcagggcg 54240 gccagcaatg acaatcatct gtccagactt caggccttgc gtgtattggt ctaggtcggg 54300 aatcccggtg ctcaaaccgt ccaacatatc gcctttctgc gctcggtcat ggcgctcctg 54360 aagcacctct acgtggtcgc gcagaatgtc tccaaccatt tggcactcac cggtagtacc 54420 acccgcatcc aaaccgagta caagggcctg agcctgagcg atcttgtctt cgattgagca 54480 attctgatgg gcaacctcct cgatcccgct ggctacatca actatctggc gcgagatagc 54540 tcgctcacga acgatccgcg cgtactcttt ggcattcgcc acgctgacga tgttggttag 54600 aatttctccg acgtaagcca tcgtgcgcgt gtcgtcgcaa aggaactctt tggcctctgc 54660 gagggtgatg atgtcaatcg gcgtgccggc ggactcgaga tcaagaatca gccggtacag 54720 gtctgcgttg acgctgtatg cgaacgcatc aggggaaagc tcttccgaca gaacgctgat 54780 cagatgaggc tgcttgagca tggcgccaag cacgccgtgc tccgcctcca ggctgtgaag 54840 ttcgatcatg cctgctcctc caactgtcgg aacacggcac gcgagcagat cacctcaagg 54900 cgcggcatga cattggctcc gcgataccag acctggctca agcgattggc ccgctcgaac 54960 acggtcttcc acagcgggct cgcctggtgc ttatcgctct cgttccagcg ctcgacgatc 55020 agggcgcgga gaaccttgtc accagccacc gaaacggccg gcaggttcgg acaggagcgg 55080 tggtacaggt cgatgatctt gtcgacagga acgccagcct cgctcacggc cttttcggcg 55140 ctccttgcca gccatttgac caggaacatg cgccagttct tcttggcctt gcggggattt 55200 gcagcggccc acacagcagc ccgagcaatc tccgcctcaa cgtcaaccgg agaatacgct 55260 ttagcccatt tggtaatcag ggctggttcg acttgaaagt cctcaccatc gaacgaaacc 55320 ccattggact tctcgacggg ctggtgatcg gccccctggg gggcggaaat ctgttccgaa 55380 ggaacagttt cagggggtag atcttttttc tttgtataga gaagggagtg agcaattttg 55440 gtctcactca cctttccgcc gattgagatc acattgtctg agtgagatga tttggtctca 55500 ctgagactgt ctttcttctg ttcgtggaat acccattcgc tggaaggaga aacaccaagc 55560 tcgccacggc ttcctccgat gcggaacagg atgcgcctct ccagcagatg gctgatcgcc 55620 ttggacacaa cgtcgcggcg catgttggtc agcgcgccaa tctcgtcggc ggttaggcgc 55680 tttgcctcaa cttgataccc aatcgtctgg cggcatatcg cgaaaagtac gcggaactcg 55740 cgggcaggca agtcaacctt ggccagcgac tccatcaagc tgttttccat ccgggtaaac 55800 cccccggtgt tgcgtaaaga aacgatattg ctcatactcg gtccgtccgt ttgctatttc 55860 ccaagcgtga ttcggctgcc accgatccac gcaccgacaa agccctgtag tagtcgctca 55920 gggctttgtt gtatctgcgc ctccactcac tcgaacccat acccgccagc tcttcagcag 55980 cgttagccat tgcggcgtag tcagaattcg tgagacgagg gcgcatgctc agacgctcac 56040 caggcgaggc ttgcgtcgca tctggtcaat catccgcaga gcctcttctg tcgcggcgcg 56100 agactcagag agttcacggt gagcctcttg cagctcacct tcatcagcgc catcaactag 56160 gctcgcaatt gcctgctgtg cttcgccgtt ctctttgatc agggatcgga gcatgcagag 56220 cacttcccgc tcgccgccct ctccatcgat caggcgaacc gataccccga ccggggtcag 56280 caggtcgccc aaggcctgaa tcttcaaatc gttcgggaga gcggacagga tcgacggcag 56340 gaaatttgcc ggaagcaggt tgttgtcctt cgtggagtca tccagccagc ggaacacccg 56400 atcggcattc gccttcatcc tgtccatcgc atcacgcgaa ggagggtcga atacgattcc 56460 ggtggcgata tgagcgttga tgcgttcgtg agcctccacg atgtgctgga ccacggtctc 56520 gcggctccag ccttcgcggc ggcgccattg gttcaccacg ccgagcagcg tggagatcag 56580 ggtgtgcgat tcgcttcgca tgctttgtgg cctcccggcc ggtagattgg atcgggttag 56640 gcggcggact gctcagtagc gaccttcagg gcgcctttcg taatgcgctc aatctcgtac 56700 tggcggagtt ttggaatttc ttctggccac tggcgcaccg cctcataggt aatgccgagg 56760 gctttggcta ccttcgaaac gccgcggaag tggctgatca cttgggtctt ggtcataggc 56820 gactccagtt cactcgcacc aattcaagca tgcttgcaat tacaaagcaa gcatgcttgg 56880 caagctacct tgtagatttc tcaacatgaa aaccacagac cggattacca agctcgtact 56940 cgccagaaag ccggagatcg gcccccgcgg ggtaaagcga gatatcgcca acacgtgcgg 57000 catcagctat gaggccgtga ggcaatggtt tgccggcgac actgaaaaca tcagaaatga 57060 aaatttgacc gctctggccg agggctatga cacgacggtg gactggcttc tatctggttc 57120 aggagagcca cctagacgaa aagcaacgag cagtgcggca gagaagttcc ttcaaatgtt 57180 gcaaggcaaa aagcttcgtc ccgatcagca gcagcgcttg gagcaggcag tgctagacac 57240 tctggatgat cagcccgtgg tggaggccgc agacaatgtg atcatcgccg acttctcccg 57300 caagccactg gtgggcgatg agattcgcat cgctcattac gatgttcagg gggcgatggg 57360 caatggaaag gttgttcaag atttcccaga gatgttccgc gatgtcacgg tcagccagca 57420 gcatctgcgc gaacttggcg ttaagtacaa ggacccatca catctgaaga taatcactgg 57480 cgacggacag tcgatggccc cgaccatcca gaacctagat ccgctaatcg tcgatgccag 57540 cattcgcgag ttcaccggcg acggtatcta cgcgttcacc tggcagggac tcttctatat 57600 caagcgccta cagttgaaag ggtcagacca cttcaagatg atctcggaca atacaagcca 57660 ccctccagag gatattcgag tggatgaaac ctacattcag gccagagtgt tgctggtctg 57720 gaacgcgaaa aggctgtgat gggcagaggc atcgcatcat aggcaaggtc atctggaggg 57780 gtggggattt gtagtcatgc tctggcgcgg cgctgtggct atggcagatt gtgggggagt 57840 aatgggcgca atcagagact ggacggaatg actcctgcac ctgaaatccg agcaaatgat 57900 ctggtaagag aacgccaggt tattcagcag aagcttcgag agactctaga gttcgatgag 57960 ctaagggcga agcggcttga gcggcagttg attattgagc gcgacaggcc tcgcgcaagc 58020 gacattatcc gtgctggcat gtggcatgaa ttggcctatc tgagcgcatt tgcagggcgg 58080 actgagcagg cactgagtcg gctggatgag acgcagcgta ttgggtttga tgatcttggc 58140 ataatacttt cgcgagcgtt catccttgag atgggtggac gtctcaccga agctcgcgat 58200 gtaattgaga tgcttgatgc tgctaacatc attgaaccat ccaggaaatt cctggtgcct 58260 cattacatgg agctgggcat gttcaaatcg gccacagaga ttgtcaccga catagaggag 58320 tacgacccgt acgccctggt ggcgaaagca attctcgaag aacatggcgt tgacgatctt 58380 gaagtgacga aaaggcttga gttcgccgcc tccatggtca tccaaagagt tggacatccg 58440 ctagttgact ataagctctt cgccatgcgc ggcgaaggaa ttctctatca gatcgtcgca 58500 aaaggcagca tagaggagct aggcaaactt ggagtagagc tgtcggatgc attggtcgat 58560 aacttcgatg gcgtattgaa cgagattctt tgcatcgatg taatcccatt tgttcctggc 58620 aaccagtcga ggcagatgga ggtgtttcgt gtcagtgtct agcgatgaca tcctgaggat 58680 tgcaaggtct ctacttggcg atgcagatga ggccttttcg cgaacatcca ttggacgctc 58740 ctactatgca gcctttcatg aagcgcgcgg aactgtcgaa agactttctc tcgctgcatc 58800 ccaaggaata ttaggcggat cacacgagaa gctgattggc gcttttgaag gaaagggccg 58860 cggtctggca aaaatcgcag cccgattgag gctgaggaag cttgccaggc agaaagctga 58920 ttacgatatc gacgaagaca tcacccccga agaagcagcg ctacatctcc accactgcga 58980 gctccttatt gacgacctgc ggcgtctaaa caagtcatga accagcccct cacccgcggg 59040 cttttcgacc cttgccacct ttgatagatt ccttccgccg gcctgggaag acagcagccc 59100 ggcaacaggc cgcgcctcga ctccagtgcg gccttttcac atcagccgcg catttgttac 59160 attgaggcgt ccttgaaggc acaacaccga aaggactagg ccgcgccgga gccttccccg 59220 gcgcggcctt ttcgttcctg cccttccctc ccggctctgc gctgagctga cgacagccct 59280 gccccggcgc ttgacgcgct acggctccct catagccgcc tcacattgag ttgtagtgcc 59340 actagcggta ttctttggcc tgtagcttgc tcgggagagc cgcatggccc gcacgaaggt 59400 tcctttctcc aaggtggcaa tgctcagcct ggcgctgagc gtttcgacct cgtgcgccca 59460 gttggcagcg gcaaccccca atctggatag tcagaagccc agcaagcaac atcagcagca 59520 ggagcttgct aagaaggcca agatccgcga gcgcatcaag cgcgccatgg ccgctctcgg 59580 ccaattgcgc gataccctcg aagcatcctg caaaatcatg ctggagcata aggtgcctga 59640 ctcgctgata aatgagcagc ccttcaccga ggtggtgcat accttgcgcc agctagaaga 59700 ggttgttcct gccgatagcg cactctcgag actgccagta atcggcgaag agtacgacgc 59760 ctttcgccgc aacctggcta aggttcgcgc catggccgtg cagaacgagg ttctcttcaa 59820 acagcaaatc accgttcctg aagtcttcca gagtgacgta agcggtgaag gactcaaatc 59880 tctggccgac ctcggcaccg aacgcctgca tcgcctggtg agctgatcac caggatggcg 59940 gtgattgtcg agttcaatcc agaaacctac gccgagctct tccaggacgt cctgaaggat 60000 ttcccttctc tccttgatgg tctctgccgc gattttgccc gctacatcga atctgatcgt 60060 ctctggctgc caccctattt cgggcgtgat gtgccatatg tcgtgccgca ggaggcttat 60120 cgcgccggcc tgatgcacat ccacatcgct attcctccca cggtattccc ggccaaccga 60180 cctcagcgtg acagaacctg cccgaacagt gctccgcaac aggacgccgc cctggtttac 60240 gtccaggggt tattcgagga aaaccgctac tccctgcttg ccctccttca ccctgatgcc 60300 catggtaagg ctcgccagcg cgagatgatg acctaccttg cccgtgtcgc cagccgcttc 60360 cgcgataaat actgatcccc ttcccgcctg acaccacaac caaagcccgc ctagcgcggg 60420 ctttttcatg gaatcagaat ggggtctcat cctcttccgc gccctcttcc acaggctcaa 60480 cctcgggaca gatagcttga tgctcaccct cgttcctaag cgcccaccgc aaggtcactg 60540 agccatcatc gttgaaaatc agctcaactc catcctcctc cgcaatcagc tccatcacgg 60600 cctcccacgc ctcgtccgta tcagtatcta gccggtgaac agtcaccgcg cgttctagct 60660 gcgccttcgg cgcattgatc attgccgaca ccctcagtcc taggcgatcc acagccgtga 60720 gttcctgctg gagttgctgc gctttcttct gcttggccat aagcccctcc ttgtactgtt 60780 cattcataca gtattaaaaa tcatcacaag attgcttgca ttctaaaaac aagcatgctt 60840 ttataaatgc aagccggctt gtgaacagca caagcaatac agcgaaggca caacaccgcc 60900 ggccaggcca ccgagccga 60919 <210> 2 <211> 627 <212> DNA <213> P. aeruginosa phage <400> 2 atgatcgagc agcgtagtga tgaatggttc gcacagcgcc tggggcgggt gacggccagc 60 aaggtcaagg atgtgatggc aaaggggcgc agtggcgccc cttctgctac ccgccagaac 120 tacatgatgc agctcctgtg cgagcgcctg accggcaagc gcgaggaagg attcaccagc 180 gccgcaatgc agcgtggtac cgaactggag ccgattgctc gctcggccta cgagttcaat 240 gcaggcgtaa tgacgatcga aacaggcctg atcatccatc cgcgaatcga tggatttggc 300 gcgtcgccag atggcctcgc gggggagcat gggctcgtcg agattaaatg cccgtctacc 360 gcaacccaca tctacacgat gcagtcgggc aagcacgacc cacagtacga gtggcagatg 420 ctcgcccaaa tgtcatgcag cggccgcgag tgggtcgact tcgtgagctt cgacgaccgt 480 ctgcctgatg aattgcagta cgtgtgcttc cgctaccacc gcgacgagga acgcattcgc 540 gagatggagt ccgaagttaa agcgttcctg gaagagttgg cagagcttga acatcagatg 600 cgagagcgca tgaggaaagc agcatga 627 <210> 3 <211> 450 <212> DNA <213> P. aeruginosa phage <400> 3 atgagaggtg ttaacaaagt cattctggtt ggtaacgtcg gtggtgaccc ggaaacccgc 60 tacatgccca acggcaatgc ggtgaccaac atcaccctcg ccaccagcga gagctggaag 120 gacaagcaga ccggccagca acaggaacgc gccgagttcc accgcgtggt gttcttcggt 180 cgcctggcgg agatcgccgg cgagtacctg cgcaagggtt cccaggtcta cgtcgaaggc 240 agcctgcgca cccgcaagtg gcaggctcag gacggccagg accgatacac caccgaggta 300 atcgtcgaca tgcacggaca gatgcagatg cttggcgcca agcctggaaa tgaccaggcg 360 gctcagagca ggccgtctca gcaggcaccg cagcagcgcc cacaggttgc gcaggattac 420 gacagcttcg acgacgatat cccgttctaa 450 <210> 4 <211> 516 <212> DNA <213> P. aeruginosa phage <400> 4 atgactgaat ggcgcgaagt ggttggttat gaaggactat accgagtatc agagcatggc 60 gaagtcatcg gggttatacg caaaaagatc aaaaagcaat tccccaatac tagcggatac 120 atgtcagtag gtctgtgcgc caatggcagg cagaagaaca ccacggtcca caaaattgtg 180 gccttggcgt tcctagataa ggccttcgag tcgctagaag taaatcacat agacggagat 240 aagctaaata atcatcactc aaatctagaa tgggttacgc gcttggaaaa tctaaatcat 300 gcaaaaaaga tggggcttct tagagagtcc accaaggtag tcgcaatgcc catagacggc 360 tcggttggat atttcttcgt atccatcaat caagccgtta agagtggatt taataacgga 420 aacatttaca actccataaa cgggaaatcc ccaaatcaca aaggcttcaa ttgggcgaaa 480 gtgcctagtg aaatgcagat aggtgaacag ccatga 516 <210> 5 <211> 435 <212> DNA <213> P. aeruginosa phage <400> 5 atgcgtacat cccaacgagg catagacctc atcaaatcct tcgagggcct gcgcctgtcc 60 gcctatcagg actcggtagg cgtttggacc attggctacg gcaccacgcg gggcgtcacc 120 cgctacatga cgatcaccgt cgagcaggcc gagcggatgc tgtcgaacga cattcagcgc 180 ttcgagcccg agatggacaa gctggtgaaa gtgccactga accagaacca gtgggatgcc 240 ctgatgagct tcgtgtacaa ccttggcgcg gccaatctgg cgtcgtccac gctgctcaag 300 ctgctgaaca agggggacta ccagggagca gcggaccagt tccctcgctg ggtgaatgcg 360 ggtggtaagc gcttggaggg tctggtcaag cgtcgagcgg cggagcgcgc gctgttcctg 420 gagccgctgt cgtga 435 <210> 6 <211> 303 <212> DNA <213> P. aeruginosa phage <400> 6 atgatcatca cattgtcacc gtactatccg ctgccaggca gcggcgaacg cctatcgctg 60 agcagggctg gcgatgtgct caccgtgaac ggccaggcgt tcgacttcac accgttaccg 120 gagggtggcg aactgccggc cgaggcgatt ggatcagagt ggttcgctgg tcccgcagtg 180 cgacgtgccg accggctgga actgagcctg cggttcccgc tggctgatga tgcaagtgcc 240 gccgctcgca ttcctgaacc gttgctgatc gatgccgatg gacctgtgga gttaccgcga 300 tga 303 <210> 7 <211> 3021 <212> DNA <213> P. aeruginosa phage <400> 7 atgacgacca tagctgagct tggcgtacgg gtgaactcgc aaggcgttga ccaggcggct 60 caggatctgg atcgcttggc tggttccgcc gtcagtgcgg aaagcgcggt tgattcagtc 120 ggagaaacct ctgcccaagc atccgcacgt atctccaata tggttcgcgc ctcgctagag 180 gctagtgatt accatcagag gcttgcgaag gcggctacca gcagtagcgc agccctcgag 240 aaggcgaatg cctcgaccat cgactggacc aagtaccagg aggagatcaa cgctcgcggg 300 caagccatca tccagtctca gcagcgcatt gccgaacagg ccaagaagtc cgctaccgca 360 gttcaggagc aatctaccgg tctcgatgcc ggcagccgga accttgccag gttcaacgat 420 cagttgggtc ggaccggcct taccgccagg caaacccagg ccgctatgcg ggggcttccc 480 gcgcagttta cggacatatt caccagcctc caggctggtc agtcgccaat gcaggtattt 540 ttgcagcaag gcggtcaaat caaagactcg tttggcggga ttggcccggc tctgcgggcg 600 gttggtgggt atgcgctgag cttgattaac ccaattaccg gattggctgc tgctgccggc 660 acgcttggct ttgctttcta cgacgcagag aaaaaggctg cctccttcag caaagctatc 720 tttgctggga atggcgcggc aggcatgact gggtcggctc tggcccaagt tgctaagcag 780 gctgcttcgg tctccggatc attggccagc gcgaatcgag ctgctattgc attggcagcc 840 agcggaaagg ttggggccgg ccaactccag agcctcacgg aaacgactag cgcaatcgct 900 caatttaccg ggcgggatat tgaggatgtg gcgaagtcct tgtcagagct gggggatgat 960 gcgactaggg cagcggcacg agttagcgag cagtatcggc tgctgagtta cgagcaatat 1020 caggcgatca aggcgatcga tgagcaaggc gaccatcagc aggctgtcga tcaactgaac 1080 gaggatctgc atcgtaacgc tcaggagagg ctgaaacagt atcgcgagtc tctgtctggt 1140 gttgagcagg gatgggacgc agttaaaacg gcgatcggta atgcctacgc tgcaatccgt 1200 gctgacttgt ttccaaccct caatgagcaa atacagacgc tccaacggac attggatcaa 1260 cggcaaaacg ctccgtttct gtcgaatgct ttgcgtggcg cactaactgg cgccgcaact 1320 ggcttgcctg gcgtggccgc taccggagca ctatttcagt cctttcggga tcagttcagc 1380 tccacagagg cattgaagga gcagaacagc ctcttgctcg tccgaaaaga cttgtccgag 1440 cagaatgcca agtcggaggc tgagctgggc gaggctgacc agcagctcat cgccattgag 1500 aaagagctgg gcgaccagtt aggcaacgtc tccccggcgg ccaagcgagc gaaagccatt 1560 gatgagctga ccaagaggta cgtcgccggc taccgcgcgg ccgagaagat gatctcggca 1620 ggcaagttga gcgcgcttcc cgactggctc aagggtgtga atattgtcgg tgatagcgta 1680 tcaggcggaa ccttcgacaa gctggtggct ggcatcaatc agcggttcaa ggacccgaag 1740 gcggccaggt cttctcaatt tcgtgatgat gctgctaccc agtacctgtt gcgtctgcgc 1800 gagcagcagg gagccctgga gcagcaactt ggtaccagcg agaaactgtc cgcttcgcag 1860 cgtgagatgg cgaagtggga gcagcagatt gcggacctga aggtgaaagc tgtcctgact 1920 gccgatcaaa agtctctctt ggctagggag gcggaggttc gcgcgcagct tcagaagaac 1980 gtggcgctcg aggccgaggc gaggaagaag gaggaaatcg ccaggatcga cgcgtaccgc 2040 gcaaaccttg aggggcgcct gcgctcagtg cagcaggggt acgaactgca gatcgctggc 2100 cttggtgcgg gcgatgaaga gcgccggcgc attcaggacc gtttgaagct ggagcaggag 2160 taccagagcc agagcgccaa actgcaggag cagcgcaacc gcggcgaaac caacggcggt 2220 atcagccaga gccagtacga aaaggaactc tctgctctgg acgattatca ccgtaaggcg 2280 ctggccaagc agaacgacta cttccatcaa gtcgatgagg ctcagaagga ttggtcgctg 2340 ggagccagat cggcgttcaa gacctatctg gaaagtgctc gggacgtggc gggccaaacc 2400 aagagcctgc tcaccaacgc gttcagcagc gcggaggact caatcgccaa cttcgccacg 2460 accggcaagc tgtcgttctc cgacttcgcc aagagcatcc tggcggacat ggcgcggatt 2520 gcaacgcgcg ccgctgcctc gcaggccctt tcgtccctct tcggcggctt cttcggcggt 2580 ggaaacgctg ccgcgcagtc gggtgtcgac aacctggtga gcaacagcgg gctgttcgcc 2640 aacggtggtg cgttcgccgg cggcgtgcag atgttcgcca ctggcggggc cttcaccaac 2700 agcgtggtca gcacgccaac cgcgttcggc atgagcggcg gccgcctggg tgtgatgggc 2760 gaagcggggc cagaggcagt gatgccgctg accagaacct cgtccggcgc cctcggtgtg 2820 cgcgctatgg gcggcggcgg ttcgcagatc aacgtcgagg tgaacattgc ctcggatggt 2880 tcggccaacg tctccagcag ccagcctggc ctggaccagt tcggtcgcga catcgggacg 2940 ttcgtcgagc agaaataccg acaactcctg gcgcgtgatc tgcggcgtga cggtgcgatc 3000 ggccgggcca tcaacgggta g 3021 <210> 8 <211> 981 <212> DNA <213> P. aeruginosa phage <400> 8 atggcacttt ccgatatgga ggtgttcaac acctatttca tgccggccac cgtcgagacg 60 ctgagccaga tggttgagcg attcaatgcg gcgtccggtg gcgcgatcct tctgaccact 120 gacggcttcg acggcgactt cctgcaaacc agtttctatg caggcctggc aggggctcgc 180 cgtcgcgtga accgctacgg ctcgaatgac gcagtaactc cggttgatct gacccagctg 240 aagcacaata ccgtcaaggt ggctggtggc ttcggcccgg ttcgatacga accatcccaa 300 atgacctggc tgcgcaagcc gactgctgaa ggtgtcgaag tcgcctcccg ctacttcgcc 360 gagtctcttc tgcaggatca gttgaacaca gccgttgccg ccctggtagc cgccatcagc 420 aaccaaggcg ccgctaccac tgtcgacgtg tccgatgcca agaaagtgga ctacattgcg 480 gtcaacgata gccacgcgct gttcggcgac cactctagcc agctcatcgc gcaagttatg 540 gatggtgccc agttccacac cttcattggc cagaatctga ccaacgctca gcaactgttc 600 caatccaacg gcgtgcgcgt ggtggatatc ctcggtcgct tgatcgtggt gaccgatgcc 660 ccggcgctct acaccccagc agtgaccgat ccggctgctc ctgccaagcg tcgcgtactc 720 tcgctgaccc aaggcgccgc aactgtccac gatgcccgag acctgatctc gaacatcgag 780 accagcaacg gcaaagagcg catcgagacc actctgcaga tcgactacag cttcggcgta 840 gggctgcgcg ggtatgcctg ggatgtagct aatggtgggg catccccgga tgatgccgct 900 ctgtccaccg gagccaactg ggacaaggtt gcaaccagtg tgaagcatac cgctggcgtt 960 ctggctgtcg gccaggccta a 981 <210> 9 <211> 417 <212> DNA <213> P. aeruginosa phage <400> 9 atggctgacc gcacattccg cattcaaggt gccgcaggta ttcgtcctgc cttcctcgcc 60 gcttggaacc tcatccaggg gctcatgcgt gacgctcagg gcggctacga actggtcctg 120 cgcccgctca agtcgaagcg ctccatcgag cagaacaagc gctactggtc ccttctacgc 180 gagcttgcat cggttgcctg ggtcgacaac cgacagttcg acgatcaggt ctggcacgag 240 cagttcaagc gctggtttat cggctgcgag gatgttgcgc tgcctgacgg ctctaccgaa 300 ctgcgcggaa tcagtacgac gaagctgagc gtcgacgagt tcggcattta catgaccaag 360 atcgaagcat gggccgctga gcaagggtgg ccgctgatga tacaggaggc cgcatga 417 <210> 10 <211> 210 <212> DNA <213> P. aeruginosa phage <400> 10 ttggctgaca tcgccgatat cgccaacgac tacgccgagc gtgaactcgc tgagcgcctg 60 tactcccgag tcaagtacgt cggcgagagc ctgcacgagt gtgaagactg cggcgaggaa 120 atcccggtag cgcggcgctc gatcgtccct ggtgttcgta aatgccggga ctgcgctgaa 180 cgggctgagc ggagggcgcg caatggctga 210 <210> 11 <211> 1341 <212> DNA <213> P. aeruginosa phage <400> 11 atgatcgaac ttcacagcct ggaggcggag cacggcgtgc ttggcgccat gctcaagcag 60 cctcatctga tcagcgttct gtcggaagag ctttcccctg atgcgttcgc atacagcgtc 120 aacgcagacc tgtaccggct gattcttgat ctcgagtccg ccggcacgcc gattgacatc 180 atcaccctcg cagaggccaa agagttcctt tgcgacgaca cgcgcacgat ggcttacgtc 240 ggagaaattc taaccaacat cgtcagcgtg gcgaatgcca aagagtacgc gcggatcgtt 300 cgtgagcgag ctatctcgcg ccagatagtt gatgtagcca gcgggatcga ggaggttgcc 360 catcagaatt gctcaatcga agacaagatc gctcaggctc aggcccttgt actcggtttg 420 gatgcgggtg gtactaccgg tgagtgccaa atggttggag acattctgcg cgaccacgta 480 gaggtgcttc aggagcgcca tgaccgagcg cagaaaggcg atatgttgga cggtttgagc 540 accgggattc ccgacctaga ccaatacacg caaggcctga agtctggaca gatgattgtc 600 attgctggcc gccctgcaat gggtaaaacc accctggcaa tgaatatcgc agcagacgtg 660 gccatcaagc agggaaggcc tgttctggtg gtcagccttg agatgacaaa ggctcaattg 720 atggatcgcc tgatcgcggc tgtcggaggc atctctctgc aaaacctgaa agatggttcc 780 tgcactcaca aagattacac cgagctcaac gcggcagtcc tcaagctccg ggacgcaaag 840 atcgccgtga gcgacgtgcc tgtaatgacg atgccgcgca tacggtccat cgcccgccga 900 cagaagcatc gcatgggcga cctggggctg atcgtcatcg actacctagg actcgtagag 960 ggcgatggca aggggcgtgt agatgacgta accaccatgt cgcgtcagat gaagctgttg 1020 gcaagggaga ttgggtgtcc tgtgcttccc ctctgccagc taaaccgagg gtgcgagtct 1080 cgccccgaca agcgtccggt cctcagcgac ctgcgcgagt ccggcgccat tgagcaagac 1140 gccgacatcg tcatgttcgt gtaccgcgat gaagtctatt tcccgaacag cgacaggaag 1200 ggtatcggcg aaatcctgat ccggaagaac cgggacggag agatcggcag cgtattcacc 1260 tccttccagg ggagcaaatc ccgattcgtc ccgcttgcaa gccactaccg cgaacagccc 1320 gagcagaagg aggactggtg a 1341 <210> 12 <211> 834 <212> DNA <213> P. aeruginosa phage <400> 12 atgaaaacca cagaccggat taccaagctc gtactcgcca gaaagccgga gatcggcccc 60 cgcggggtaa agcgagatat cgccaacacg tgcggcatca gctatgaggc cgtgaggcaa 120 tggtttgccg gcgacactga aaacatcaga aatgaaaatt tgaccgctct ggccgagggc 180 tatgacacga cggtggactg gcttctatct ggttcaggag agccacctag acgaaaagca 240 acgagcagtg cggcagagaa gttccttcaa atgttgcaag gcaaaaagct tcgtcccgat 300 cagcagcagc gcttggagca ggcagtgcta gacactctgg atgatcagcc cgtggtggag 360 gccgcagaca atgtgatcat cgccgacttc tcccgcaagc cactggtggg cgatgagatt 420 cgcatcgctc attacgatgt tcagggggcg atgggcaatg gaaaggttgt tcaagatttc 480 ccagagatgt tccgcgatgt cacggtcagc cagcagcatc tgcgcgaact tggcgttaag 540 tacaaggacc catcacatct gaagataatc actggcgacg gacagtcgat ggccccgacc 600 atccagaacc tagatccgct aatcgtcgat gccagcattc gcgagttcac cggcgacggt 660 atctacgcgt tcacctggca gggactcttc tatatcaagc gcctacagtt gaaagggtca 720 gaccacttca agatgatctc ggacaataca agccaccctc cagaggatat tcgagtggat 780 gaaacctaca ttcaggccag agtgttgctg gtctggaacg cgaaaaggct gtga 834

Claims (14)

카바페넴(carbapenem)에 대해 내성을 갖는 녹농균(Pseudomonas aeruginosa)에 대하여 특이적 세포 사멸능을 가지며, 서열번호 2 내지 12 중 적어도 하나로 표시되는 유전체를 포함하는 박테리오파지 [KCTC18363P]. Bacteriophage [KCTC18363P] comprising a genome represented by at least one of SEQ ID NOS: 2 to 12, having specific cytotoxicity against Pseudomonas aeruginosa resistant to carbapenem. 제1항에 있어서,
상기 박테리오파지 [KCTC18363P]는 서열번호 1로 표시되는 유전체로 이루어진 것인, 박테리오파지 [KCTC18363P].The method according to claim 1,
Wherein said bacteriophage [KCTC18363P] is comprised of the genome of SEQ ID NO: 1. 삭제delete 삭제delete 삭제delete 카바페넴(carbapenem)에 대해 내성을 갖는 녹농균(Pseudomonas aeruginosa)에 대하여 특이적 세포 사멸능을 가지며, 서열번호 2 내지 12 중 적어도 하나로 표시되는 유전체를 포함하는 박테리오파지 [KCTC18363P]를 유효 성분으로 포함하는, 폐렴, 뇌수막염, 균혈증, 심내막염 및 내인성 기회감염으로 이루어진 군에서 선택되는 항생제 내성 슈도모나스(Pseudomonas)속 균주 유발성 질환의 예방 또는 치료용 약학적 조성물. A bacteriophage [KCTC18363P] having a specific cytotoxicity against Pseudomonas aeruginosa resistant to carbapenem and comprising a genome represented by at least one of SEQ ID NOS: 2 to 12, A pharmaceutical composition for preventing or treating an antibiotic-resistant Pseudomonas sp. Strain-induced disease selected from the group consisting of pneumonia, meningitis, bacteremia, endocarditis and endogenous opportunistic infection. 제6항에 있어서,
상기 박테리오파지 [KCTC18363P]는 서열번호 1로 표시되는 유전체로 이루어진 것인, 약학적 조성물.The method according to claim 6,
Wherein said bacteriophage [KCTC18363P] is comprised of a dielectric of SEQ ID NO: 1. 삭제delete 삭제delete 삭제delete 삭제delete 제1항 또는 제2항의 박테리오파지 [KCTC18363P]를 유효성분으로 포함하는 항생제.An antibiotic comprising the bacteriophage [KCTC18363P] of claim 1 or 2 as an active ingredient. 제1항 또는 제2항의 박테리오파지 [KCTC18363P]를 유효성분으로 포함하는 소독제.A disinfectant comprising the bacteriophage [KCTC18363P] of claim 1 or 2 as an active ingredient. 카바페넴(carbapenem)에 대해 내성을 갖는 녹농균(Pseudomonas aeruginosa)에 대하여 특이적 세포 사멸능을 가지며, 서열번호 2 내지 12 중 적어도 하나로 표시되는 유전체를 포함하는 박테리오파지 [KCTC18363P]를 유효 성분으로 포함하는, 폐렴, 뇌수막염, 균혈증, 심내막염 및 내인성 기회감염으로 이루어진 군에서 선택되는 항생제 내성 슈도모나스(Pseudomonas)속 균주 유발성 질환 개선용 식품 조성물. A bacteriophage [KCTC18363P] having a specific cytotoxicity against Pseudomonas aeruginosa resistant to carbapenem and comprising a genome represented by at least one of SEQ ID NOS: 2 to 12, Pseudomonas aeruginosa, Pneumonia, Meningitis, Bacteremia, Endocarditis, and Endogenous opportunistic infections.
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GenBank: HG530068.1, 2015.02.27.
GenBank: HG798806.1, 2014.04.10.
PLoS ONE 9 (4), E93777 (2014).

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