KR102482440B1 - 부계 ube3a 발현을 유도하기 위한 올리고뉴클레오티드 - Google Patents

부계 ube3a 발현을 유도하기 위한 올리고뉴클레오티드 Download PDF

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KR102482440B1
KR102482440B1 KR1020207033999A KR20207033999A KR102482440B1 KR 102482440 B1 KR102482440 B1 KR 102482440B1 KR 1020207033999 A KR1020207033999 A KR 1020207033999A KR 20207033999 A KR20207033999 A KR 20207033999A KR 102482440 B1 KR102482440 B1 KR 102482440B1
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oligonucleotide
antisense oligonucleotide
nucleosides
ube3a
lna
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KR1020207033999A
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KR20200137027A (ko
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베로니카 코스타
마이 헤트요른
마리우스 회너
라비 자가시아
마스 오보에 옌센
크리스토프 파치
뤼케 페데르센
쇠렌 베스테르고르 라스무쎈
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에프. 호프만-라 로슈 아게
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Priority to KR1020227045154A priority Critical patent/KR20230008233A/ko
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Abstract

본 발명은 동물 또는 인간 뉴런에서 부계 대립유전자로부터 유비퀴틴-단백질 리가제 E3A(UBE3A)의 발현을 유도할 수 있는 올리고뉴클레오티드에 관한 것이다. 상기 올리고뉴클레오티드는 SNORD109B 하류의 SNHG14 긴 비-암호화 RNA에 하이브리드화됨으로써 UBE3A 부계 대립유전자의 억제유전자를 표적화한다. 본 발명은 또한 엔젤만 증후군의 치료를 위한 약학 조성물 및 방법에 관한 것이다.

Description

부계 UBE3A 발현을 유도하기 위한 올리고뉴클레오티드{OLIGONUCLEOTIDES FOR INDUCING PATERNAL UBE3A EXPRESSION}
본 발명은 SNORD109B 하류의 SNHG14에 상보적이고 그에 하이브리드화되어, 동물 또는 인간에서 유비퀴틴-단백질 리가제 E3A(UBE3A)의 부계 발현의 유도를 이끄는 올리고뉴클레오티드(올리고머)에 관한 것이다. 본 발명은 또한 엔젤만 증후군(Angelman syndrom)의 치료를 위한 약학 조성물 및 방법에 관한 것이다.
엔젤만 증후군은 모계 유전 염색체 15q11.2 상의 UBE3A 유전자의 결실 또는 불활성화에 의해 야기된 신경-유전적 장애이다. UBE3A 유전자의 부계 카피는 SNHG14로 지칭되는 UBE3A의 내인성 안티센스 전사체(UBE3A-ATS로도 알려져 있음)에 의한 뉴런에서의 게놈 각인 및 침묵의 대상이다[Meng et al. 2012 Hum Mol Genet. Vol. 21 pp. 3001-12]. 뉴런 이외의 다른 세포 유형들은 모계 및 부계 대립유전자 둘 다로부터 UBE3A 유전자를 발현하는 것으로 보인다.
엔젤만 증후군은 심한 지적 및 발달 장애, 수면 장애, 발작, 경련성 동작, EEG 이상, 과도한 웃음 또는 미소, 및 심한 언어 장애를 특징으로 한다.
WO 2012/064806 호는 토포이소머라제 억제제를 사용하여 세포에서 UBE3A 발현을 유도하는 방법을 개시하고 있다. 상기 방법은 엔젤만 증후군을 치료하기 위해 사용될 수 있다. 안티센스 올리고뉴클레오티드에 대한 개시내용은 없다.
WO 2014/004572 호는 마우스 UBE3A-ATS를 표적화하는 2'-O-메톡시에틸-RNA (MOE) 변형을 갖는 올리고뉴클레오티드를 개시하고 있다. 상기 올리고뉴클레오티드는 마우스 관련 분석들에서만 시험되었다. MBII-52 snoRNA(SNORD115로도 알려져 있음)의 하류 및 UBE3A 전구체-mRNA의 상류 영역에서는 마우스와 인간 사이에서 보존되지 않는다. 그러므로, 마우스 UBE3A-ATS를 표적화하는 올리고뉴클레오티드는 인간에서 기능할 올리고뉴클레오티드로 변환될 수 없다. 인간 UBE3A-ATS를 표적화하는 올리고뉴클레오티드에 대한 개시내용은 없다.
본 발명은 부계 SNORD115, SNORD116 및 SNRPN 전사체의 발현에 유의미하게 영향을 미치지 않으면서 뉴런에서 인간 부계 UBE3A 발현을 유도하는 새로운 올리고뉴클레오티드를 확인한다.
본 발명은, UBE3A의 발현을 억제할 수 있는 핵산을 표적화하고 특히 뉴런 세포에서 UBE3A의 감소된 활성과 관련된 질환을 치료하거나 예방하기 위한 올리고뉴클레오티드에 관한 것이다.
따라서, 첫번째 양태에서, 본 발명은 인간 염색체 15 버전 GRCh38.p2 상의 위치 25278410 내지 25419462에 상응하는 인간 SNHG14 긴 비-암호화 RNA 부분에 대해 98% 이상의 상보성을 갖는, 10 내지 30개 뉴클레오티드 길이의 연속 뉴클레오티드 서열을 포함하는 올리고뉴클레오티드를 제공한다. 상기 영역은 또한 서열번호 1로 나타낸다. 상기 올리고뉴클레오티드는, 바람직하게는 갭머(gapmer) 디자인을 갖는 안티센스 올리고뉴클레오티드일 수 있다. 바람직하게, 상기 올리고뉴클레오티드는, UBE3A 억제유전자의 분해, 감소 또는 제거에 의해, 특히 SNORD109B의 하류의 SNHG14 긴 비-암호화 RNA 전사체의 감소에 의해, 뉴런에서 UBE3A의 발현, 특히 부계 UBE3A 발현을 유도할 수 있다. UBE3A 재발현은 SNORD115의 발현에 유의미하게 영향을 미치지 않으면서 달성된다. 표적 핵산의 분해는 바람직하게는 뉴클레아제 구성에 의해 달성된다.
또 다른 양태에서, 본 발명은 본 발명의 올리고뉴클레오티드 및 약학적으로 허용되는 희석제, 담체, 염 및/또는 보조제를 포함하는 약학 조성물을 제공한다.
또 다른 양태에서, 본 발명은, 부계 UBE3A의 발현이 억제되는 표적 세포에 본 발명의 올리고뉴클레오티드 또는 조성물을 효과량으로 투여함으로써 상기 표적 세포에서 UBE3A 발현을 생체내 또는 시험관내에서 유도하기 위한 방법을 제공한다.
또 다른 양태에서, 본 발명은, UBE3A의 생체내 활성과 연관된 질환, 장애 또는 기능장애를 앓고 있거나 또는 상기 질환, 장애 또는 기능장애에 걸리기 쉬운 대상에게 본 발명의 올리고뉴클레오티드를 치료 또는 예방 효과량으로 투여하는 것을 포함하는, UBE3A의 생체내 활성과 연관된 질환, 장애 또는 기능장애를 치료하거나 예방하는 방법을 제공한다.
또 다른 양태에서, 본 발명의 올리고뉴클레오티드 또는 조성물은 엔젤만 증후군의 치료 또는 예방에 사용된다.
도 1: 위쪽 가닥은 SNORD109B의 하류의 SNHG14 전사체의 영역(UBE3A-ATS)을 나타내는 것으로, 여기서 검정색 박스는 검사한 마우스 올리고뉴클레오티드의 위치를 나타낸다. 아래쪽 가닥은 UBE3A 암호화 영역을 나타내며, 여기서 검정색 박스는 엑손을 나타낸다. 엑손 1은 대략 160 kb에 위치한다. 올리고뉴클레오티드는 엑손 9(약 97 kb에 위치), 엑손 10(약 92 kb에 위치), 엑손 13(약 77 kb에 위치)의 안티센스 영역 및 엑손 16(약 60 kb에 위치)의 5' 말단에 위치한다.
도 2: 실시예 2에서 검사한, 인간 뉴런 세포 배양물에서 UBE3A의 발현을 유도하는 올리고뉴클레오티드의 능력을 나타낸 것이다. SNORD109B와 UBE3A 암호화 영역의 상류 영역 사이의 인간 SNHG14 긴 비-암호화 RNA의 영역(서열번호 1의 위치 1 내지 55318)에 상보적인 올리고뉴클레오티드는 *비중복으로 표시되어 있다. UBE3A 전구체-mRNA에 대해 안티센스인 인간 SNHG14 긴 비-암호화 RNA의 영역(서열번호 1의 위치 55319 내지 141053)에 상보적인 올리고뉴클레오티드는 ▲중복으로 표시되어 있다. 인간 및 붉은털 원숭이에 대해 보존되는 표 3의 올리고뉴클레오티드들은 각 도표의 바닥에 ▩로 표시되어 있다. 인간:붉은털 원숭이:마우스 사이의 보존은 ■로 표시되어 있다. 올리고뉴클레오티드 농도는 각 도표의 우변에 표시된 바와 같이 0.2, 1 및 5 μM이었다.
정의
올리고뉴클레오티드
본원에서 사용된 바와 같이 용어 "올리고뉴클레오티드"는, 숙련된 자에 의해 2개 이상의 공유결합된 뉴클레오시드를 포함하는 분자로서 일반적으로 이해되는 바와 같이 정의된다. 상기 공유결합된 뉴클레오시드는 또한 핵산 분자 또는 올리고머로 지칭될 수 있다. 올리고뉴클레오티드는 통상적으로 고체상 화학 합성후 정제시킴으로써 실험실에서 제조된다. 올리고뉴클레오티드의 서열을 언급할 때, 상기 언급은 공유 결합된 뉴클레오티드 또는 뉴클레오시드의 핵염기 잔기들 또는 그의 변형들의 서열 또는 순서에 대한 것이다. 본 발명의 올리고뉴클레오티드는 인공이며, 화학적으로 합성되고, 전형적으로 정제되거나 단리된다. 본 발명의 올리고뉴클레오티드는 1개 이상의 변형된 뉴클레오시드 또는 뉴클레오티드를 포함할 수 있다.
안티센스 올리고뉴클레오티드
본원에서 사용된 바와 같이 용어 "안티센스 올리고뉴클레오티드"는 표적 핵산, 특히 표적 핵산 상의 연속 서열에 하이브리드화됨으로써 표적 유전자의 발현을 조절할 수 있는 올리고뉴클레오티드로서 정의된다. 안티센스 올리고뉴클레오티드는 반드시 이중 가닥인 것은 아니며 따라서 siRNA가 아니다. 바람직하게, 본 발명의 안티센스 올리고뉴클레오티드는 단일 가닥이다.
연속 뉴클레오티드 서열
용어 "연속 뉴클레오티드 서열"은 표적 핵산에 상보적인 올리고뉴클레오티드의 영역을 말한다. 상기 용어는 본원에서 용어 "연속 핵염기 서열" 및 용어 "올리고뉴클레오티드 모티프 서열"과 상호교환적으로 사용된다. 일부 실시양태에서, 올리고뉴클레오티드의 모든 뉴클레오티드들은 연속 뉴클레오티드 서열에 존재한다. 일부 실시양태에서, 올리고뉴클레오티드는 연속 뉴클레오티드 서열을 포함하며, 선택적으로 추가의 뉴클레오티드(들), 예를 들면, 작용기를 연속 뉴클레오티드 서열에 결합시키기 위해 사용될 수 있는 뉴클레오티드 링커 영역을 포함할 수 있다. 상기 뉴클레오티드 링커 영역은 표적 핵산에 상보적일 수 있거나 아닐 수 있다.
뉴클레오티드
뉴클레오티드는 올리고뉴클레오티드 및 폴리뉴클레오티드의 구성 요소이며, 본 발명의 취지에서 천연 및 비-천연 뉴클레오티드를 둘 다 포함한다. 사실상, DNA 및 RNA 뉴클레오티드와 같은 뉴클레오티드는 리보스 당 잔기, 핵염기 잔기 및 1개 이상의 포스페이트 기(뉴클레오시드에는 부재함)를 포함한다. 뉴클레오시드 및 뉴클레오티드는 또한 "단위" 또는 "단량체"로서 상호교환적으로 지칭될 수 있다.
변형된 뉴클레오시드
본원에서 사용된 바와 같이 용어 "변형된 뉴클레오시드" 또는 "뉴클레오시드 변형"은 당 잔기 또는 (핵)염기 잔기의 하나 이상의 변형의 도입에 의해 등가의 DNA 또는 RNA 뉴클레오시드와 비교하여 변형된 뉴클레오시드를 말한다. 바람직한 실시양태에서, 변형된 뉴클레오시드는 변형된 당 잔기를 포함한다. 용어 변형된 뉴클레오시드는 또한 본원에서 용어 "뉴클레오시드 유사체" 또는 변형된 "단위" 또는 변형된 "단량체"와 상호교환적으로 사용될 수 있다.
변형된 뉴클레오시드간 결합
용어 "변형된 뉴클레오시드간 결합"은 숙련된 자에 의해 2개의 뉴클레오시드를 서로 공유적으로 결합시키는, 포스포다이에스터(PO) 결합 이외의 다른 결합으로서 일반적으로 이해되는 바와 같이 정의된다. 변형된 뉴클레오시드간 결합을 갖는 뉴클레오티드는 또한 "변형된 뉴클레오티드"로 지칭된다. 일부 실시양태에서, 변형된 뉴클레오시드간 결합은 포스포다이에스터 결합에 비해 올리고뉴클레오티드의 뉴클레아제 내성을 증가시킨다. 천연 올리고뉴클레오티드의 경우, 뉴클레오시드간 결합은 인접 뉴클레오시드들 사이에 포스포다이에스터 결합을 생성하는 포스페이트 기들을 포함한다. 변형된 뉴클레오시드간 결합은 생체내 사용을 위해 올리고뉴클레오티드를 안정화시키는데 특히 유용하며, 본 발명의 올리고뉴클레오티드 중 DNA 또는 RNA 뉴클레오시드들의 영역에서, 예를 들면, 갭머 올리고뉴클레오티드의 갭 영역내에서 뿐 아니라 변형된 뉴클레오시드의 영역들에서 뉴클레아제 절단에 대해 보호하는 역할을 할 수 있다.
한 실시양태에서, 올리고뉴클레오티드는 천연 포스포다이에스터로부터, 예를 들면, 뉴클레아제 공격에 더 내성인 결합으로 변형된 뉴클레오시드간 결합을 1개 이상 포함한다. 뉴클레아제 내성은, 올리고뉴클레오티드를 혈청중에서 배양하거나 또는 뉴클레아제 내성 분석(예를 들면, 뱀독 포스포다이에스터라제(SVPD))에 의해 측정할 수 있으면, 상기 두 방법은 모두 당해분야에 공지되어 있다. 올리고뉴클레오티드의 뉴클레아제 내성을 증대시킬 수 있는 뉴클레오시드간 결합은 뉴클레아제 내성 뉴클레오시드간 결합으로 지칭된다. 바람직한 실시양태에서, 올리고뉴클레오티드 또는 그의 연속 뉴클레오티드 서열 중 뉴클레오시드간 결합의 50% 이상, 예를 들면, 올리고뉴클레이티드 또는 그의 연속 뉴클레오티드 서열 중 뉴클레오시드간 결합의 60% 이상, 예를 들면, 70% 이상, 예를 들면, 80% 이상 또는 예를 들면, 90% 이상이 변형된다. 일부 실시양태에서, 올리고뉴클레오티드 또는 그의 연속 뉴클레이티드 서열의 뉴클레오시드간 결합 모두가 변형된다. 일부 실시양태에서, 본 발명의 올리고뉴클레오티드를 비-뉴클레오티드 작용기, 예를 들어, 접합체에 결합시키는 뉴클레오시드는 포스포다이에스터일 수 있음을 인지할 것이다. 일부 실시양태에서, 올리고뉴클레오티드 또는 그의 연속 뉴클레이티드 서열의 뉴클레오시드간 결합 모두는 뉴클레아제 내성 뉴클레오시드간 결합이다.
변형된 뉴클레오시드간 결합은 포스포로티오에이트, 다이포스포로티오에이트 및 보라노포스페이트를 포함하는 군에서 선택될 수 있다. 바람직한 실시양태에서, 변형된 뉴클레오시드간 결합, 예를 들면, 포스포로티오에이트, 다이포스포로티오에이트 또는 보라노포스페이트는 본 발명의 올리고뉴클레오티드의 RNaseH 구성과 양립가능하다.
일부 실시양태에서, 뉴클레오시드간 결합은 포스포로티오에이트 뉴클레오시드간 결합과 같이 황(S)을 포함한다.
포스포로티오에이트 뉴클레오시드간 결합은 뉴클레아제 내성, 유리한 약동학 및 제조의 용이성으로 인해 특히 유용하다. 바람직한 실시양태에서, 올리고뉴클레오티드 또는 그의 연속 뉴클레오티드 서열 중 뉴클레오시드간 결합의 50% 이상이 포스포로티오에이트이다, 예를 들면, 올리고뉴클레이티드 또는 그의 연속 뉴클레오티드 서열 중 뉴클레오시드간 결합의 60% 이상, 예를 들면, 70% 이상, 예를 들면, 80% 이상 또는 예를 들면, 90% 이상이 포스포로티오에이트이다. 일부 실시양태에서, 올리고뉴클레오티드 또는 그의 연속 뉴클레오티드 서열 중 뉴클레오시드간 결합 모두가 포스포로티오에이트이다.
일부 실시양태에서, 올리고뉴클레오티드는 1개 이상의 중성 뉴클레오시드간 결합, 특히 포스포트라이에스터, 메틸포스페이트, MMI, 아미드-3, 폼아세탈 또는 티오폼아세탈로부터 선택된 뉴클레오시드간 결합을 포함한다.
또 다른 뉴클레오시드간 결합은 WO2009/124238 호(본원에 참고로 도입됨)에 개시되어 있다. 한 실시양태에서, 뉴클레오시드간 결합은 WO2007/031091 호(본원에 참고로 도입됨)에 개시된 링커들로부터 선택된다. 특히, 뉴클레오시드간 결합은 -O-P(O)2-O-, -O-P(O,S)-O-, -O-P(S)2-O-, -S-P(O)2-O-, -S-P(O,S)-O-, -S-P(S)2-O-, -O-P(O)2-S-, -O-P(O,S)-S-, -S-P(O)2-S-, -O-PO(RH)-O-, 0-PO(OCH3)-0-, -O-PO(NRH)-O-, -O-PO(OCH2CH2S-R)-O-, -O-PO(BH3)-O-, -O-PO(NHRH)-O-, -O-P(O)2-NRH-, -NRH-P(O)2-O-, -NRH-CO-O-, -NRH-CO-NRH-로부터 선택될 수 있고/있거나, 뉴클레오시드간 링커는 -O-CO-O-, -O-CO-NRH-, -NRH-CO-CH2-, -O-CH2-CO-NRH-, -O-CH2-CH2-NRH-, -CO-NRH-CH2-, -CH2-NRHCO-, -O-CH2-CH2-S-, -S-CH2-CH2-O-, -S-CH2-CH2-S-, -CH2-SO2-CH2-, -CH2-CO-NRH-, -O-CH2-CH2-NRH-CO-, -CH2-NCH3-O-CH2-로 이루어진 군에서 선택될 수 있으며, 이때 RH는 수소 및 C1-4-알킬로부터 선택된다.
뉴클레아제 내성 결합, 예를 들면, 포스포티오에이트 결합은, 표적 핵산과 이중체를 형성할 때 뉴클레아제를 구성할 수 있는 올리고뉴클레오티드 영역, 예를 들면, 갭머의 경우 영역 G, 또는 헤드머(headmer) 및 테일머(tailmer)의 비-변형된 뉴클레오시드 영역에 특히 유용하다. 그러나, 포스포로티오에이트 결합은 또한 갭머의 경우 영역 F 및 F', 또는 헤드머 및 테일머의 변형된 뉴클레오시드 영역과 같은 비-뉴클레아제 구성 영역 및/또는 친화도 증대 영역에도 유용할 수 있다.
그러나, 상기 디자인 영역들 각각은, 특히 LNA와 같은 변형된 뉴클레오시드가 뉴클레아제 분해에 대해 결합을 보호하는 영역에 포스포로티오에이트 이외의 다른 뉴클레오시드간 결합, 예를 들면, 포스포다이에스터 결합을 포함할 수 있다. 특히 변형된 뉴클레오시드 단위들 사이에 또는 상기 단위들에 인접하여 포스포다이에스터 결합, 예를 들면, 1개 또는 2개 결합의 혼입은 올리고뉴클레오티드의 생체이용률 및/또는 생체분포를 변화시킬 수 있다 - 본원에 참고로 도입된 WO2008/113832 호 참조.
한 실시양태에서, 올리고뉴클레오티드 중 모든 뉴클레오시드간 결합은 포스포로티오에이트 및/또는 보라노포스페이트 결합이다. 바람직하게, 올리고뉴클레오티드 중 모든 뉴클레오시드간 결합은 포스포로티오에이트 결합이다.
핵염기
용어 핵염기는 핵산 하이브리드화시 수소 결합을 형성하는 뉴클레오시드 및 뉴클레오티드에 존재하는 퓨린(예, 아데닌 및 구아닌) 및 피리미딘(예, 우라실, 티민 및 시토신) 잔기를 포함한다. 본 발명의 맥락에서, 용어 핵염기는 천연 핵염기와 상이할 수 있지만 핵산 하이브리드화시 기능성인 변형된 핵염기를 또한 포함한다. 이와 관련하여, "핵염기"는 아데닌, 구아닌, 시토신, 티미딘, 우라실, 잔틴 및 하이포잔틴과 같은 천연 핵염기뿐 아니라 비천연 변이체 둘 다를 말한다. 상기 변이체들은, 예를 들면, 문헌 [Hirao et al (2012) Accounts of Chemical Research vol 45 page 2055 and Bergstrom (2009) Current Protocols in Nucleic Acid Chemistry Suppl. 37 1.4.1]에 기술되어 있다.
일부 실시양태에서, 핵염기 잔기는, 퓨린 또는 피리미딘을 변형된 퓨린 또는 피리미딘, 예를 들면, 치환된 퓨린 또는 치환된 피리미딘, 예를 들어, 이소시토신, 슈도이소시토신, 5-메틸 시토신, 5-티오졸로-시토신, 5-프로피닐-시토신, 5-프로피닐-우라실, 5-브로모우라실 5-티아졸로-우라실, 2-티오-우라실, 2'티오-티민, 이노신, 디아미노퓨린, 6-아미노퓨린, 2-아미노퓨린, 2,6-디아미노퓨린 및 2-클로로-6-아미노퓨린으로부터 선택된 핵염기로 변화시킴으로써 변형된다.
핵염기 잔기는 각각의 상응하는 핵염기를 암호화는 문자, 예를 들면, A, T, G, C 또는 U로 나타낼 수 있으며, 이때 각각의 문자는 선택적으로 등가의 기능을 갖는 변형된 핵염기를 포함할 수 있다. 예를 들면, 예시된 올리고뉴클레오티드에서, 핵염기 잔기는 A, T, G, C, 및 5-메틸 시토신으로부터 선택된다. 선택적으로, LNA 갭머의 경우, 5-메틸 시토신 LNA 뉴클레오시드가 사용될 수 있다.
변형된 올리고뉴클레오티드
용어 변형된 올리고뉴클레오티드는 1개 이상의 당-변형된 뉴클레오시드 및/또는 변형된 뉴클레오시드간 결합을 포함하는 올리고뉴클레오티드를 설명한다. 용어 "키메라" 올리고뉴클레오티드는 변형된 뉴클레오시드를 갖는 올리고뉴클레오티드를 기술하기 위해 문헌에서 사용된 용어이다.
상보성
용어 상보성은 뉴클레오시드/뉴클레오티드의 왓슨-크릭(Watson-Crick) 염기-쌍형성에 대한 능력을 설명한다. 왓슨-크릭 염기쌍은 구아닌(G)-시토신(C) 및 아데닌(A) - 티민(T)/우라실(U)이다. 올리고뉴클레오티드는 변형된 핵염기를 갖는 뉴클레오시드를 포함할 수 있음을 이해할 것이다, 예를 들면, 5-메틸 시토신이 시토신 대신에 종종 사용되고, 따라서 용어 상보성은 비-변형 핵염기와 변형 핵염기 사이에 왓슨 크릭 염기-쌍형성을 포함한다(예를 들면, 문헌 [Hirao et al (2012) Accounts of Chemical Research vol 45 page 2055 and Bergstrom (2009) Current Protocols in Nucleic Acid Chemistry Suppl. 37 1.4.1] 참조).
본원에서 사용된 바와 같이 용어 "%상보성"은, 주어진 위치에서, 별개 핵산 분자(예, 표적 핵산)의 주어진 위치에서 연속 뉴클레오티드 서열에 상보적인(즉, 연속 뉴클레오티드 서열과 왓슨 크릭 염기쌍을 형성하는) 핵산 분자(예, 올리고뉴클레오티드) 중 연속 뉴클레오티드 서열의 퍼센트로서 뉴클레오티드의 수를 말한다. 상기 백분율은, 2개의 서열들 사이에서 쌍을 형성하는 정렬된 염기들의 수를 계수하고, 올리고뉴클레오티드 중 뉴클레오티드의 총수로 나누고, 100을 곱함으로써 산출된다. 상기 비교에서, 정렬되지 않는(염기쌍을 형성하지 않는) 핵염기/뉴클레오티드는 미스매치로 지칭된다.
용어 "완전히 상보적인"은 100% 상보성을 말한다.
하이브리드화
본원에서 사용된 바와 같이 용어 "하이브리드화되는" 또는 "하이브리드화되다"는 대향 가닥들 상의 염기쌍들 사이에 수소 결합을 형성함으로써 이중체를 형성하는 2개의 핵산 가닥(예를 들면, 올리고뉴클레오티드 및 표적 핵산)으로 이해해야 한다. 2개 핵산 가닥들 사이의 결합의 친화도는 하이브리드화의 강도이다. 상기 친화도는 종종 올리고뉴클레오티드들의 절반이 표적 핵산과 이중체화되는 온도로 정의되는 용융 온도(Tm)의 견지에서 기술된다. 생리학적 조건에서, Tm은 친화도와 엄격하게 비례하지는 않는다[Mergny and Lacroix, 2003,Oligonucleotides 13:515-537]. 표준 상태 깁스(Gibbs) 자유 에너지 ΔG°는 결합 친화도를 보다 정확하게 나타내는 것이며, ΔG°=-RTln(Kd)에 의한 반응의 해리 상수(Kd)와 관련되며, 이때 R은 기체 상수이고 T는 절대 온도이다. 그러므로, 올리고뉴클레오티드와 표적 핵산 사이 반응의 매우 낮은 ΔG°는 올리고뉴클레오티드와 표적 핵산 사이의 강한 하이브리드화를 반영한다. ΔG°는, 수용액 농도가 1 M이고 pH가 7이고 온도가 37 ℃인 반응과 연관된 에너지이다. 올리고뉴클레오티드의 표적 핵산에 대한 하이브리드화는 자발적 반응이며, 자발적 반응의 경우 ΔG°는 0(제로)보다 낮다. ΔG°는 실험적으로, 예를 들면, 문헌 [Hansen et al., 1965, Chem. Comm. 36-38 and Holdgate et al., 2005, Drug Discov Today]에 기술된 바와 같은 등온 적정 열량측정(TIC) 방법을 이용하여 측정할 수 있다. 숙련된 자라면 상업적 장비가 ΔG° 측정을 위해 이용가능함을 알 것이다. ΔG°는 또한, 문헌 [Sugimoto et al., 1995, Biochemistry 34:11211-11216 and McTigue et al., 2004, Biochemistry 43:5388-5405]에 기술된 적절히 유도된 열역학 파라미터들을 이용하여 문헌 [SantaLucia, 1998, Proc Natl Acad Sci USA. 95: 1460-1465]에 기술된 바와 같은 최근린(nearest neighbor) 모델을 이용함으로써 수치적으로 평가될 수 있다. 하이브리드화에 의한 그의 의도한 핵산 표적을 조절할 가능성을 갖기 위해, 본 발명의 올리고뉴클레오티드는, 10 내지 30개 뉴클레오티드 길이의 올리고뉴클레오티드에 대해 -10 kcal 미만의 평가된 ΔG°값하에 표적 핵산에 하이브리드화된다. 일부 실시양태에서, 하이브리드화의 정도 또는 강도는 표준 상태 깁스 자유 에너지 ΔG°에 의해 측정된다. 올리고뉴클레오티드는 8 내지 30개 뉴클레오티드 길이의 올리고뉴클레오티드에 대해 -10 kcal 범위 미만, 예를 들면, -15 kcal 미만, 예를 들어 -20 kcal 미만 및 예를 들어, -25 kcal 미만의 평가된 ΔG°값하에 표적 핵산에 하이브리드화될 수 있다. 일부 실시양태에서, 상기 올리고뉴클레오티드는 -10 내지 -60 kcal, 예를 들면, -12 내지 -40, 예를 들어, -15 내지 -30 kcal 또는 -16 내지 -27 kcal, 예를 들어, -18 내지 -25 kcal의 평가된 ΔG°값하에 표적 핵산에 하이브리드화된다.
표적
표적은 조절하는 것을 목적하는 단백질을 말한다.
표적 핵산
표적 핵산은 본 발명의 올리고뉴클레오티드가 그에 하이브리드화되는 의도된 표적이며, 예를 들면, 유전자, RNA, 비-암호화 RNA, 긴 비-암호화 RNA, mRNA, 및 전구체-mRNA, 성숙 mRNA 또는 cDNA 서열일 수 있다. 일부 실시양태에서, 표적 핵산은 비-암호화 RNA 또는 긴 비-암호화 RNA, 또는 그의 아서열(subsequence)이다. 생체내 또는 시험관내 용도에서, 본 발명의 올리고뉴클레오티드는 의도된 표적 세포의 SNORD109B 하류의 SNHG14 전사체의 수준을 감소시킴으로써 상기 의도된 표적 세포에서 부계 UBE3A 전사체의 억제를 해제시킬 수 있다. 본 발명의 올리고뉴클레오티드의 핵염기의 연속 서열은, 선택적으로 1개 또는 2개의 미스매치를 제외하고, 선택적으로 올리고뉴클레오티드를 접합체와 같은 선택적인 작용기에 연결시킬 수 있는 뉴클레오티드 기반 링커 영역을 배제하고, 올리고뉴클레오티드의 길이 전체에 걸쳐 측정시, 표적 핵산에 상보적이다.
표적 서열
올리고뉴클레오티드는 표적 핵산 분자의 아서열에 상보적이거나 또는 그에 하이브리드화되는 연속 뉴클레오티드 서열을 포함한다. 본원에서 사용된 바와 같이 용어 "표적 서열"은 본 발명의 올리고뉴클레오티드에 상보적인 핵염기 서열을 포함하는 표적 핵산에 존재하는 뉴클레오티드의 서열을 말한다. 일부 실시양태에서, 표적 서열은 본 발명의 올리고뉴클레오티드의 연속 뉴클레오티드 서열에 상보적인 표적 핵산 상의 영역으로 이루어진다. 일부 실시양태에서, 표적 서열은 단일 올리고뉴클레오티드의 상보적 서열보다 길고, 예를 들면, 본 발명의 여러 올리고뉴클레오티드들에 의해 표적화될 수 있는 표적 핵산의 바람직한 영역을 나타낼 수 있다.
본 발명의 올리고뉴클레오티드는 표적 핵산, 예를 들면, 표적 서열에 상보적인 연속 뉴클레오티드 서열을 포함한다.
올리고뉴클레오티드는 표적 핵산 분자에 존재하는 표적 서열에 상보적이거나 상기 표적 서열과 하이브리드화되는 8개 이상의 뉴클레오티드들의 연속 뉴클레오티드 서열을 포함한다. 상기 연속 뉴클레오티드 서열(및 따라서 표적 서열)은 8개 이상의 연속 뉴클레오티드, 예를 들면, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29 또는 30 개의 연속 뉴클레오티드, 예를 들면, 12 내지 25개, 예를 들어, 14 내지 18개 연속 뉴클레오티드를 포함한다.
표적 세포
본원에서 사용된 바와 같이 용어 표적 세포는 표적 핵산을 발현할 것인 세포를 말한다. 일부 실시양태에서, 표적 세포는 생체내 또는 시험관내 세포일 수 있다. 일부 실시양태에서, 표적 세포는 포유동물 세포, 예를 들면, 마우스 세포 또는 래트 세포와 같은 설치류 세포, 또는 원숭이 세포 또는 인간 세포와 같은 영장류 세포이다. 바람직한 실시양태에서, 표적 세포는 뉴런 세포이다.
천연 변이체
용어 "천연 변이체"는 SNORD109B 유전자 하류의 SNHG14 전사체의 변이체, 또는 표적 핵산과 동일한 유전자좌로부터 유래하지만, 예를 들면, 긴 비-암호화 RNA에서 코돈의 다중성을 야기하는 유전자 코드의 퇴화로 인해 상이할 수 있는 전사체를 말한다. 그러므로, 본 발명의 올리고뉴클레오티드는 표적 핵산 및 그의 천연 변이체를 표적화하도록 설계될 수 있다.
발현의 조절
본원에서 사용된 바와 같이 용어 "발현의 조절"은, 올리고뉴클레오티드의 투여 전 UBE3A의 양에 비해 UBE3A 단백질의 양을 변화시키는 올리고뉴클레오티드의 능력에 대한 전체적인 용어로 이해해야 한다. 또는, 발현의 조절은 본 발명의 올리고뉴클레오티드가 투여되지 않는 대조군 실험을 참조하여 결정될 수 있다. 올리고뉴클레오티드에 의해 수행된 조절은, 예를 들면, SNORD109B 하류의 비-암호화 SNHG14 전사체의 분해 또는 제거에 의해 또는 SNORD109B 하류의 SNHG14 전사체와 연관된 폴리머라제 활성의 차단 또는 방지에 의해, 부계 UBE3A 전사체의 억제를 감소, 제거, 방지, 경감, 저하 또는 종료시키는 그의 능력에 관한 것이다. 상기 조절은 또한, 예를 들면, SNORD109B 하류의 비-암호화 SNHG14 전사체에 의해 영향을 받는 억제 메카니즘의 제거 또는 차단에 의해, 부계 UBE3A의 발현을 복구, 증가 또는 증대시키는 올리고뉴클레오티드의 능력으로 간주될 수 있다.
고친화성 변형 뉴클레오시드
고친화성 변형 뉴클레오시드는, 올리고뉴클레오티드 내에 혼입시, 예를 들면, 용융 온도(Tm)로 측정되는 바와 같은, 그의 상보적 표적에 대한 올리고뉴클레오티드의 친화도를 증대시키는 변형된 뉴클레오티드이다. 본 발명의 고친화성 변형 뉴클레오시드는 바람직하게는 변형된 뉴클레오시드 당 +0.5 내지 +12 ℃, 보다 바람직하게는 +1.5 내지 +10 ℃, 및 가장 바람직하게는 +3 내지 +8 ℃의 용융 온도 증가를 야기한다. 많은 고친화성 변형 뉴클레오티드가 당해 분야에 공지되어 있으며, 예를 들면, 많은 2' 치환된 뉴클레오시드뿐 아니라 잠금 핵산(LNA)을 포함한다(예를 들면, 문헌 [Freier & Altmann; Nucl. Acid Res., 1997, 25, 4429-4443 and Uhlmann; Curr. Opinion in Drug Development, 2000, 3(2), 293-213] 참조).
당 변형
본 발명의 올리고머는 변형된 당 잔기, 즉, DNA 및 RNA에서 발견되는 리보스 당 잔기와 비교시 당 잔기의 변형을 갖는 뉴클레오시드를 1개 이상 포함할 수 있다.
상기 리보스 당 잔기의 변형을 갖는 많은 뉴클레오시드들이, 주로 올리고뉴클레오티드의 특정 성질들, 예를 들면, 친화도 및/또는 뉴클레아제 내성을 개선할 목적으로 제조되었다.
상기 변형은, 리보스 고리 구조가, 예를 들면, 6탄당 고리(HNA), 또는 전형적으로 리보스 고리(LNA) 상의 C2 및 C4 탄소들 사이에 2가라디칼 가교를 갖는 바이사이클릭 고리, 또는 전형적으로 C2 및 C3 탄소 사이에 결합이 결여된 비결합 리보스 고리(예, UNA)로 치환됨으로써 변형되는 변형들을 포함한다. 다른 당 변형된 뉴클레오시드들은, 예를 들면, 바이사이클로헥소스 핵산(WO2011/017521 호) 또는 트라이사이클릭 핵산(WO2013/154798 호)을 포함한다. 변형된 뉴클레오시드는 또한 당 잔기가, 예를 들면, 펩티드 핵산(PNA) 또는 모폴리노 핵산의 경우에서 비-당 잔기로 치환되는 뉴클레오시드를 포함한다.
당 변형은 또한 리보스 고리 상의 치환체 기들을 수소가 아닌 다른 기, 또는 DNA 및 RNA 뉴클레오시드에서 천연적으로 발견되는 2'-OH 기로 변화시킴으로써 제조된 변형을 포함한다. 치환체들은, 예를 들면, 2', 3', 4' 또는 5' 위치에 도입될 수 있다. 변형된 당 잔기를 갖는 뉴클레오시드는 또한 2' 변형된 뉴클레오시드, 예를 들면, 2' 치환된 뉴클레오시드를 포함한다. 사실상, 2' 치환된 뉴클레오시드를 개발하는데 많은 초점이 맞춰져왔고, 많은 2' 치환된 뉴클레오시드들이 올리고뉴클레오티드 내에 혼입시, 증대된 뉴클레오시드 내성 및 증대된 친화도와 같은 유리한 성질을 갖는 것으로 밝혀졌다.
2' 변형된 뉴클레오시드
2' 당 변형된 뉴클레오시드는 2' 위치에 H 또는 -OH 이외의 다른 치환기를 가지거나(2' 치환된 뉴클레오시드) 또는 2' 결합된 2가 라디칼을 포함하는 뉴클레오시드이며, 2' 치환된 뉴클레오시드 및 LNA(2' - 4' 2가 라디칼 가교된) 뉴클레오시드를 포함한다. 예를 들면, 2' 변형된 당은 올리고뉴클레오티드에 증대된 결합 친화도 및/또는 증가된 뉴클레아제 내성을 제공할 수 있다. 2' 치환된 변형 뉴클레오시드의 예는 2'-O-알킬-RNA, 2'-O-메틸-RNA, 2'-알콕시-RNA, 2'-O-메톡시에틸-RNA(MOE), 2'-아미노-DNA, 2'-플루오로-RNA, 및 2'-플루오로-ANA(F-ANA)이다. 또 다른 예들에 대해서는, 예를 들면, 문헌 [Freier & Altmann; Nucl. Acid Res., 1997, 25, 4429-4443 and Uhlmann; Curr. Opinion in Drug Development, 2000, 3(2), 293-213; and Deleavey and Damha, Chemistry and Biology 2012, 19, 937]을 참조하시오. 하기는 몇몇 2' 치환된 변형 뉴클레오시드들의 예시이다.
Figure 112020127052610-pat00001
Figure 112020127052610-pat00002
잠금 핵산 뉴클레오시드(LNA)
LNA 뉴클레오시드는 뉴클레오티드의 리보스 당 고리의 C2'와 C4' 사이에 링커 기(2가 라디칼 또는 가교로 지칭됨)를 포함하는 변형된 뉴클레오시드이다. 이들 뉴클레오시드는 또한 문헌에서 가교된 핵산 또는 바이사이클릭 핵산(BNA)으로도 지칭된다.
일부 실시양태에서, 본 발명의 올리고머의 변형된 뉴클레오시드 또는 LNA 뉴클레오시드는 하기 화학식 I 또는 II의 일반 구조를 갖는다:
[화학식 I]
Figure 112020127052610-pat00003
[화학식 II]
Figure 112020127052610-pat00004
상기 식에서, W는 -O-, -S-, -N(Ra)-, -C(RaRb)-에서 선택되고, 예를 들면, 일부 실시양태에서는 -O-이고; B는 핵염기 또는 변형된 핵염기 잔기를 나타내고; Z는 인접 뉴클레오시드에 대한 뉴클레오시드간 결합, 또는 5'-말단 기를 나타내고; Z*는 인접 뉴클레오시드에 대한 뉴클레오시드간 결합, 또는 3'-말단 기를 나타내고; X는 -C(RaRb)-, -C(Ra)=C(Rb)-, -C(Ra)=N-, -O-, -Si(Ra)2-, -S-, -SO2-, -N(Ra)-, 및 >C=Z로 이루어진 목록에서 선택된 기를 나타낸다.
일부 실시양태에서, X는 -O-, -S-, NH-, NRaRb, -CH2-, CRaRb, -C(=CH2)-, 및 -C(=CRaRb)-로 이루어진 군에서 선택된다.
일부 실시양태에서, X는 -O-이다. Y는 -C(RaRb)-, -C(Ra)=C(Rb)-, -C(Ra)=N-, -O-, -Si(Ra)2-, -S-, -SO2-, -N(Ra)-, 및 >C=Z로 이루어진 군에서 선택된 기를 나타낸다.
일부 실시양태에서, Y는 CH2-, -C(RaRb)-, -CH2CH2-, -C(RaRb)-C(RaRb)-, -CH2CH2CH2-, -C(RaRb)C(RaRb)C(RaRb)-, -C(Ra)=C(Rb)-, 및 -C(Ra)=N-으로 이루어진 군에서 선택된다.
일부 실시양태에서, Y는 -CH2-, -CHRa-, -CHCH3-, CRaRb-로 이루어진 군에서 선택되거나, 또는 -X-Y-는 함께 -C(RaRb)-, -C(Ra)=C(Rb)-, -C(Ra)=N-, -O-, -Si(Ra)2-, -S-, -SO2-, -N(Ra)-, 및 >C=Z로 이루어진 군에서 선택된 1, 2, 3 또는 4개의 기/원자로 이루어지는 2가 링커 기(라디칼로도 지칭됨)를 나타낸다.
일부 실시양태에서, -X-Y-는 -X-CH2-, -X-CRaRb-, -X-CHRa-, -X-C(HCH3)-, -O-Y-, -O-CH2-, -S-CH2-, -NH-CH2-, -O-CHCH3-, -CH2-O-CH2, -O-CH(CH3CH3)-, -O-CH2-CH2-, OCH2-CH2-CH2-,-O-CH2OCH2-, -O-NCH2-, -C(=CH2)-CH2-, -NRa-CH2-, N-O-CH2, -S-CRaRb- 및 -S-CHRa-로 이루어진 군에서 선택된 2가 라디칼을 나타낸다.
일부 실시양태에서, -X-Y-는 -O-CH2- 또는 -O-CH(CH3)-을 나타낸다.
상기에서, Z는 -O-, -S-, 및 -N(Ra)-로부터 선택되고, Ra, 및 존재하는 경우, Rb는 각각 독립적으로, 수소, 선택적으로 치환된 C1-6-알킬, 선택적으로 치환된 C2-6-알케닐, 선택적으로 치환된 C2-6-알키닐, 하이드록시, 선택적으로 치환된 C1-6-알콕시, C2-6-알콕시알킬, C2-6-알케닐옥시, 카복시, C1-6-알콕시카보닐, C1-6-알킬카보닐, 포밀, 아릴, 아릴옥시-카보닐, 아릴옥시, 아릴카보닐, 헤테로아릴, 헤테로아릴옥시-카보닐, 헤테로아릴옥시, 헤테로아릴카보닐, 아미노, 모노- 및 다이(C1-6-알킬)아미노, 카바모일, 모노- 및 다이(C1-6-알킬)-아미노-카보닐, 아미노-C1-6-알킬-아미노카보닐, 모노- 및 다이(C1-6-알킬)아미노-C1-6-알킬-아미노카보닐, C1-6-알킬-카보닐아미노, 카브아미도, C1-6-알카노일옥시, 설포노, C1-6-알킬설포닐옥시, 니트로, 아지도, 설파닐, C1-6-알킬티오, 할로겐으로부터 선택되며, 이때 아릴 및 헤테로아릴은 선택적으로 치환될 수 있고, 2개의 같은자리 치환체 Ra 및 Rb는 함께, 선택적으로 치환된 메틸렌(=CH2)을 나타낼 수 있고, 여기서 모든 키랄 중심에 대해, 비대칭 기들이 R 또는 S 배향으로 확인될 수 있다.
상기에서, R1, R2, R3, R5 및 R5*는 독립적으로 수소, 선택적으로 치환된 C1-6-알킬, 선택적으로 치환된 C2-6-알케닐, 선택적으로 치환된 C2-6-알키닐, 하이드록시, C1-6-알콕시, C2-6-알콕시알킬, C2-6-알케닐옥시, 카복시, C1-6-알콕시카보닐, C1-6-알킬카보닐, 포밀, 아릴, 아릴옥시-카보닐, 아릴옥시, 아릴카보닐, 헤테로아릴, 헤테로아릴옥시-카보닐, 헤테로아릴옥시, 헤테로아릴카보닐, 아미노, 모노- 및 다이(C1-6-알킬)아미노, 카바모일, 모노- 및 다이(C1-6-알킬)-아미노-카보닐, 아미노-C1-6-알킬-아미노카보닐, 모노- 및 다이(C1-6-알킬)아미노-C1-6-알킬-아미노카보닐, C1-6-알킬-카보닐아미노, 카브아미도, C1-6-알카노일옥시, 설포노, C1-6-알킬설포닐옥시, 니트로, 아지도, 설파닐, C1-6-알킬티오, 할로겐으로 이루어진 군에서 선택되고, 이때 아릴 및 헤테로아릴은 선택적으로 치환될 수 있고, 2개의 같은자리 치환체들은 함께 옥소, 티옥소, 이미노 또는 선택적으로 치환된 메틸렌을 나타낼 수 있다.
일부 실시양태에서, R1, R2, R3, R5 및 R5*는 독립적으로 C1-6 알킬, 예를 들면, 메틸, 및 수소로부터 선택된다.
일부 실시양태에서, R1, R2, R3, R5 및 R5*는 모두 수소이다.
일부 실시양태에서, R1, R2, R3은 모두 수소이고, R5 및 R5*의 어느 하나도 또한 수소이고, R5 및 R5*의 다른 하나는 수소가 아닌 다른 기, 예를 들면, C1-6 알킬, 예를 들어, 메틸이다.
일부 실시양태에서, Ra는 수소 또는 메틸이다. 일부 실시양태에서, 존재하는 경우, Rb는 수소 또는 메틸이다.
일부 실시양태에서, Ra 및 Rb 중 하나 또는 둘 다는 수소이다.
일부 실시양태에서, Ra 및 Rb 중 하나는 수소이고, 다른 하나는 수소가 아닌 다른 기이다.
일부 실시양태에서, Ra 및 Rb 중 하나는 메틸이고, 다른 하나는 수소이다.
일부 실시양태에서, Ra 및 Rb 둘 다는 메틸이다.
일부 실시양태에서, 2가 라디칼 -X-Y-는 -O-CH2-이고, W는 O이고, R1, R2, R3, R5 및 R5* 모두는 전부 수소이다. 상기 LNA 뉴클레오시드는, 모두 본원에 참고로 도입되는 WO99/014226 호, WO00/66604 호, WO98/039352 호 및 WO2004/046160 호에 개시되어 있으며, 베타-D-옥시 LNA 및 알파-L-옥시 LNA 뉴클레오시드로 일반적으로 알려진 것들을 포함한다.
일부 실시양태에서, 2가 라디칼 -X-Y-는 -S-CH2-이고, W는 O이고, R1, R2, R3, R5 및 R5* 모두는 전부 수소이다. 상기 티오 LNA 뉴클레오시드는 본원에 참고로 도입되는 WO99/014226 호 및 WO2004/046160 호에 개시되어 있다.
일부 실시양태에서, 2가 라디칼 -X-Y-는 -NH-CH2-이고, W는 O이고, R1, R2, R3, R5 및 R5* 모두는 전부 수소이다. 상기 아미노 LNA 뉴클레오시드는 본원에 참고로 도입되는 WO99/014226 호 및 WO2004/046160 호에 개시되어 있다.
일부 실시양태에서, 2가 라디칼 -X-Y-는 -O-CH2-CH2- 또는 -O-CH2-CH2-CH2-이고, W는 O이고, R1, R2, R3, R5 및 R5* 모두는 전부 수소이다. 상기 LNA 뉴클레오시드는 본원에 참고로 도입되는 WO 00/047599 호 및 문헌 [Morita et al, Bioorganic & Med.Chem. Lett. 12 73-76]에 개시되어 있으며, 2'-O-4'C-에틸렌 가교된 핵산(ENA)으로 일반적으로 알려진 것들을 포함한다.
일부 실시양태에서, 2가 라디칼 -X-Y-는 -O-CH2-이고, W는 O이고, R1, R2, R3 모두, 및 R5 및 R5* 중 하나는 수소이고, R5 및 R5* 중 다른 하나는 수소가 아닌 다른 기, 예를 들면, C1-6 알킬, 예를 들어, 메틸이다. 상기 5' 치환된 LNA 뉴클레오시드는 본원에 참고로 도입되는 WO2007/134181 호에 개시되어 있다.
일부 실시양태에서, 2가 라디칼 -X-Y- 는 -O-CRaRb-이고, 이때 Ra 및 Rb 중 하나 또는 둘 다는 수소가 아닌 다른 기, 예를 들면, 메틸이고, W는 O이고, R1, R2, R3 모두, 및 R5 및 R5* 중 하나는 수소이고, R5 및 R5* 중 다른 하나는 수소가 아닌 다른 기, 예를 들면, C1-6 알킬, 예를 들어, 메틸이다. 상기 비스 변형된 LNA 뉴클레오시드는 본원에 참고로 도입되는 WO2010/077578 호에 개시되어 있다.
일부 실시양태에서, 2가 라디칼 -X-Y-는 2가 링커 기-O-CH(CH2OCH3)- (2' O-메톡시에틸 바이사이클릭 핵산 - [Seth at al., 2010, J. Org. Chem. Vol 75(5) pp. 1569-81])를 나타낸다. 일부 실시양태에서, 2가 라디칼 -X-Y-는 2가 링커 기 -O-CH(CH2CH3)- (2'O-에틸 바이사이클릭 핵산 - [Seth at al., 2010, J. Org. Chem. Vol 75(5) pp. 1569-81])를 나타낸다. 일부 실시양태에서, 2가 라디칼 -X-Y-는 -O-CHRa-이고, W는 O이고, R1, R2, R3, R5 및 R5* 모두는 전부 수소이다. 상기 6' 치환된 LNA 뉴클레오시드는 WO10036698 호 및 WO07090071 호에 개시되어 있고, 이들은 둘 다 본원에 참고로 도입된다.
일부 실시양태에서, 2가 라디칼 -X-Y-는 -O-CH(CH2OCH3)-이고, W는 O이고, R1, R2, R3, R5 및 R5* 모두는 전부 수소이다. 상기 LNA 뉴클레오시드는 또한 당해 분야에서 사이클릭 MOE(cMOE)로도 알려져 있으며, WO07090071 호에 개시되어 있다.
일부 실시양태에서, 2가 라디칼 -X-Y-는 R- 또는 S-입체형태의 2가 링커 기 -O-CH(CH3)-를 나타낸다. 일부 실시양태에서, 2가 라디칼 -X-Y-는 함께 2가 링커 기-O-CH2-O-CH2-[Seth at al., 2010, J. Org. Chem.]를 나타낸다. 일부 실시양태에서, 2가 라디칼 -X-Y-는 -O-CH(CH3)-이고, W는 O이고, R1, R2, R3, R5 및 R5* 모두는 전부 수소이다. 상기 6' 메틸 LNA 뉴클레오시드는 또한 당해 분야에서 cET 뉴클레오시드로도 알려져 있으며, 둘 다 본원에 참고로 도입되는 WO07090071 호(베타-D) 및 WO2010/036698 호(알파-L)에 개시된 바와 같이, (S)cET 또는 (R)cET 입체이성질체일 수 있다.
일부 실시양태에서, 2가 라디칼 -X-Y-는 -O-CRaRb-이고, 이때 Ra도 Rb도 수소가 아니며, W는 O이고, R1, R2, R3, R5 및 R5* 모두는 전부 수소이다. 일부 실시양태에서, Ra 및 Rb는 둘 다 메틸이다. 상기 6' 이치환된 LNA 뉴클레오시드는 본원에 참고로 도입되는 WO 2009006478 호에 개시되어 있다.
일부 실시양태에서, 2가 라디칼 -X-Y-는 -S-CHRa-이고, W는 O이고, R1, R2, R3, R5 및 R5* 모두는 전부 수소이다. 상기 6' 치환된 티오 LNA 뉴클레오시드는 본원에 참고로 도입되는 WO11156202 호에 개시되어 있다. 일부 6' 치환된 티오 LNA 실시양태에서, Ra는 메틸이다.
일부 실시양태에서, 2가 라디칼 -X-Y-는 -C(=CH2)-C(RaRb)-, 예를 들면, -C(=CH2)-CH2- 또는 -C(=CH2)-CH(CH3)-이고, W는 O이고, R1, R2, R3, R5 및 R5* 모두는 전부 수소이다. 상기 비닐 카보 LNA 뉴클레오시드는 WO08154401 호 및 WO09067647 호에 개시되어 있고, 이들은 둘 다 본원에 참고로 도입된다.
일부 실시양태에서, 2가 라디칼 -X-Y-는 -N(-ORa)-이고, W는 O이고, R1, R2, R3, R5 및 R5* 모두는 전부 수소이다. 일부 실시양태에서, Ra는 C1-6 알킬, 예를 들면, 메틸이다. 상기 LNA 뉴클레오시드는 또한 N 치환된 LNA로도 알려져 있으며, 본원에 참고로 도입되는 WO2008/150729 호에 개시되어 있다. 일부 실시양태에서, 2가 라디칼 -X-Y-는 함께 2가 링커 기 -O-NRa-CH3-[Seth at al., 2010, J. Org. Chem]를 나타낸다. 일부 실시양태에서, 2가 라디칼-X-Y-는 -N(Ra)-이고, W는 O이고, R1, R2, R3, R5 및 R5* 모두는 전부 수소이다. 일부 실시양태에서, Ra는 C1-6 알킬, 예를 들면, 메틸이다.
일부 실시양태에서, R5 및 R5* 중 하나 또는 둘 다는 수소이고, 치환시 R5 및 R5* 중 다른 하나는 C1-6 알킬, 예를 들면, 메틸이다. 상기 실시양태에서, R1, R2, R3는 모두 수소일 수 있고, 2가 라디칼 -X-Y-는 -O-CH2- 또는 -O-C(HCRa)-, 예를 들면, -O-C(HCH3)-로부터 선택될 수 있다.
일부 실시양태에서, 상기 2가 라디칼은 -CRaRb-O-CRaRb-, 예를 들면, CH2-O-CH2-이고, W는 O이고, R1, R2, R3, R5 및 R5* 모두는 전부 수소이다. 일부 실시양태에서, Ra는 C1-6 알킬, 예를 들면, 메틸이다. 상기 LNA 뉴클레오시드는 또한 입체형태적으로 제한된 뉴클레오시드(CRN)로도 알려져 있으며, 본원에 참고로 도입되는 WO2013036868 호에 개시되어 있다.
일부 실시양태에서, 상기 2가 라디칼은 -O-CRaRb-O-CRaRb-, 예를 들면, O-CH2-O-CH2-이고, W는 O이고, R1, R2, R3, R5 및 R5* 모두는 전부 수소이다. 일부 실시양태에서, Ra는 C1-6 알킬, 예를 들면, 메틸이다. 상기 LNA 뉴클레오시드는 또한 COC 뉴클레오티드로도 알려져 있으며, 본원에 참고로 도입되는 문헌 [Mitsuoka et al., Nucleic Acids Research 2009 37(4), 1225-1238]에 개시되어 있다.
명시되지 않는 한, LAN 뉴클레오시드는 베타-D 또는 알파-L 입체이소폼(stereoisoform)일 수 있음을 인지할 것이다.
LNA 뉴클레오시드의 특정 예는 도식 1에 나타내었다.
[도식 1]
Figure 112020127052610-pat00005
예로 예시된 바와 같이, 본 발명의 바람직한 실시양태에서, 올리고뉴클레오티드 중 LNA 뉴클레오시드는 베타-D-옥시-LNA 뉴클레오시드이다.
뉴클레아제 매개된 분해
뉴클레아제 매개된 분해는, 상보적 뉴클레오티드 서열과 이중체를 형성하는 경우, 상기 상보적 뉴클레오티드 서열의 분해를 매개할 수 있는 올리고뉴클레오티드를 말한다.
일부 실시양태에서, 올리고뉴클레오티드는 표적 핵산의 뉴클레아제 매개된 분해를 통해 작용할 수 있으며, 이때 본 발명의 올리고뉴클레오티드는 뉴클레아제, 특히 엔도뉴클레아제, 바람직하게는 엔도리보뉴클레아제(RNase), 예를 들면, RNase H를 구성할 수 있다. 뉴클레아제 매개 메카니즘을 통해 작동하는 올리고뉴클레오티드 디자인들의 예는, 전형적으로 적어도 5 또는 6개의 DNA 뉴클레오시드의 영역을 포함하고 친화도 증대 뉴클레오시드, 예를 들면, 갭머, 헤드머 및 테일머가 한쪽 또는 양쪽 측면에 위치하는 올리고뉴클레오티드이다.
RNase H 활성 및 구성
안티센스 올리고뉴클레오티드의 RNase H 활성은 상보적 RNA 분자와 이중체인 경우 RNase H를 구성하는 그의 능력을 말한다. WO 01/23613 호는, RNaseH를 구성하는 능력을 측정하기 위해 사용될 수 있는, RNaseH 활성을 측정하는 시험관내 방법을 제공하고 있다. 전형적으로, 올리고뉴클레오티드는, 상보적 표적 핵산 서열이 제공될 때, 시험되는 변형 올리고뉴클레오티드와 동일한 염기 서열을 갖지만, 올리고뉴클레오티드내 모든 단량체들 사이에 포스포로티오에이트 결합과 함께 DNA 단량체만을 함유하는 올리고뉴클레오티드를 사용하고 WO 01/23613 호(본원에 참고로 도입됨)의 실시예 91 내지 95에 제공된 방법을 이용한 경우 측정된 초기 속도의 10% 이상 또는 20%보다 큰, pmol/l/분으로 측정된 바와 같은 초기 속도를 갖는 경우, RNase H를 구성할 수 있는 것으로 간주된다.
갭머
본원에서 사용된 바와 같이 용어 갭머(gapmer)는 하나 이상의 친화도 증대 변형 뉴클레오시드(측면서열)가 5' 및 3' 측면에 위치하는 RNase H 구성 올리고뉴클레오티드의 영역(갭)을 포함하는 안티센스 올리고뉴클레오티드를 말한다. 다양한 갭머 디자인들이 본원에서 기술된다. 헤드머(headmer) 및 테일머(tailmer)는 측면서열들 중 하나가 소실되는 경우 RNase H를 구성할 수 있는 올리고뉴클레오티드이다, 즉, 상기 올리고뉴클레오티드의 말단들 중 하나만이 친화도 증대 변형 뉴클레오시드를 포함한다. 헤드머의 경우, 3' 측면서열이 소실되고(즉, 5' 측면서열이 친화도 증대 변형 뉴클레오시드를 포함한다), 테일머의 경우 5' 측면서열이 소실된다(즉, 3' 측면서열이 친화도 증대 변형 뉴클레오시드를 포함한다).
LNA 갭머
용어 LNA 갭머는 친화도 증대 변형 뉴클레오시드 중 적어도 하나가 LNA 뉴클레오시드인 갭머 올리고뉴클레오티드이다.
혼합 날개서열 갭머
용어 혼합 날개서열 갭머(mixed wing gapmer)는, 측면서열 영역들이 1개 이상의 LNA 뉴클레오시드 및 1개 이상의 비-LNA 변형 뉴클레오시드, 예를 들면, 1개 이상의 2' 치환된 변형 뉴클레오시드, 예를 들어, 2'-O-알킬-RNA, 2'-O-메틸-RNA, 2'-알콕시-RNA, 2'-O-메톡시에틸-RNA(MOE), 2'-아미노-DNA, 2'-플루오로-RNA 및 2'-F-ANA 뉴클레오시드(들)을 포함하는 LNA 갭머를 말한다. 일부 실시양태에서, 혼합 날개서열 갭머는 LNA 뉴클레오시드를 포함하는 1개의 측면서열(예를 들면, 5' 또는 3')을 가지고, 다른 측면서열(3' 또는 5' 각각)는 2' 치환된 변형 뉴클레오시드(들)을 포함한다.
접합체
본원에서 사용된 바와 같이 용어 접합체는 비-뉴클레오티드 잔기(접합체 잔기 또는 영역 C 또는 제 3 영역)에 공유 결합된 올리고뉴클레오티드를 말한다.
하나 이상의 비-뉴클레오티드 잔기에 대한 본 발명의 올리고뉴클레오티드의 접합은, 예를 들면, 올리고뉴클레오티드의 활성, 세포내 분포, 세포내 흡수 또는 안정성에 영향을 미침으로써 올리고뉴클레오티드의 약리학을 개선시킬 수 있다. 일부 실시양태에서, 접합체 잔기는 올리고뉴클레오티드의 세포내 분포, 생체이용률, 대사, 분비, 투과성 및/또는 세포내 흡수를 개선시킴으로써 올리고뉴클레오티드의 약동학적 성질을 조절하거나 증대시킨다. 특히, 접합체는 올리고뉴클레오티드를 특정 장기, 조직 또는 세포 유형으로 표적화시킬 수 있으며, 이에 의해 상기 장기, 조직 또는 세포 유형 내에서 상기 올리고뉴클레오티드의 효과성을 증대시킬 수 있다. 동시에, 상기 접합체는 비-표적 세포 유형, 조직 또는 장기에서 올리고뉴클레오티드의 활성, 예를 들면, 표적이탈(off target) 활성 또는 비-표적 세포 유형, 조직 또는 장기에서의 활성을 감소시키는 역할을 할 수 있다. 본원에 참고로 도입되는 WO 93/07883 호 및 WO 2013/033230 호는 적당한 접합체 잔기를 제공한다. 본원에 참고로 도입되는 WO 2012/143379 호는 트랜스페린 수용체에 대한 친화도를 갖는 항체 단편에 대한 접합에 의해 혈액-뇌-장벽을 가로질러 약물을 전달하는 방법을 제공한다.
올리고뉴클레오티드 접합체 및 그의 합성은 또한, 각각 본원에 전체적으로 참고로 도입되는 문헌 [Manoharan in Antisense Drug Technology, Principles, Strategies, and Applications, S.T. Crooke, ed., Ch. 16, Marcel Dekker, Inc., 2001 and Manoharan, Antisense and Nucleic Acid Drug Development, 2002, 12, 103]에 종합적 고찰에서 보고되었다.
한 실시양태에서, 비-뉴클레오티드 잔기(접합체 잔기)는 탄수화물, 세포 표면 수용체 리간드, 약물 물질, 호르몬, 친유성 물질, 중합체, 단백질, 펩티드, 독소(예, 세균 독소), 비타민, 바이러스 단백질(예, 캡시드) 또는 이들의 조합으로 이루어진 군에서 선택된다. 일부 실시양태에서, 비-뉴클레오티드 잔기는 항체 또는 항체 단편, 예를 들면, 혈액-뇌-장벽을 가로지른 전달을 촉진하는 항체 또는 항체 단편, 특히 트랜스페린 수용체를 표적화하는 항체 또는 항체 단편이다.
링커
결합 또는 링커는 관심 대상인 1개의 화학 기 또는 분절을 1개 이상의 공유 결합을 통해 관심대상인 또 다른 화학 기 또는 분절에 연결시키는 2개 원자 사이의 연결이다. 접합체 잔기는 직접적으로 또는 결합 잔기(예, 링커 또는 테더(tether))를 통해 올리고뉴클레오티드에 결합될 수 있다. 링커는 제 3 영역, 예를 들면, 접합체 잔기(영역 C)를 제 1 영역, 예를 들면, 올리고뉴클레오티드(영역 A)에 공유적으로 연결시키는 역할을 한다.
본 발명의 일부 실시양태에서, 본 발명의 접합체 또는 올리고뉴클레오티드 접합체는 선택적으로, 올리고뉴클레오티드(영역 A 또는 제 1 영역)과 접합체 잔기(영역 C 또는 제 3 영역) 사이에 위치하는 링커 영역(제 2 영역 또는 영역 B 및/또는 영역 Y)을 포함할 수 있다.
영역 B는 포유동물 신체내에서 통상적으로 접하게되는 조건하에서 또는 접하게 되는 조건과 유사한 조건하에서 절단성인 생리적으로 불안정한 결합을 포함하거나 그로 이루어지는 생체절단성 링커를 말한다. 생리적으로 불안정한 링커가 화학적 변형(예, 절단)이 일어나는 조건은 pH, 온도, 산화 또는 환원성 조건 또는 약제들, 및 포유동물 세포에서 발견되는 염 농도 또는 포유동물 세포에서 접하게 되는 바와 유사한 염 농도와 같은 화학적 조건들을 포함한다. 포유동물 세포내 조건은 또한 단백질분해 효소 또는 가수분해 효소 또는 뉴클레아제와 같은 포유동물 세포에 통상적으로 존재하는 효소 활성의 존재를 포함한다. 한 실시양태에서, 생체절단성 링커는 S1 뉴클레아제 절단에 민감하다. 바람직한 실시양태에서, 뉴클레아제 민감성 링커는 1 내지 10개의 뉴클레오시드, 예를 들면, 1, 2, 3, 4, 5, 6, 7, 8, 9 또는 10개 뉴클레오시드, 보다 바람직하게는 2 내지 6개의 뉴클레오시드, 및 가장 바람직하게는 2개 이상의 연속 포스포다이에스터 결합, 예를 들면, 적어도 3개 또는 4개 또는 5개의 연속 포스포다이에스터 결합을 포함하는, 2 내지 4개의 결합된 뉴클레오시드를 포함한다. 바람직하게, 뉴클레오시드는 DNA 또는 RNA이다. 포스포다이에스터 함유 생체절단성 링커는 WO 2014/076195 호(본원에 참고로 도입됨)에 보다 상세히 기술되어 있다.
영역 Y는 반드시 생체절단성은 아니지만 주로 접합체 잔기(영역 C 또는 제 3 영역)를 올리고뉴클레오티드(영역 A 또는 제 1 영역)에 공유적으로 연결시키는 역할을 하는 링커를 말한다. 영역 Y 링커는 에틸렌 글리콜, 아미노산 단위 또는 아미노 알킬기와 같은 반복 단위들의 쇄 구조 또는 올리고머를 포함할 수 있다. 본 발명의 올리고뉴클레오티드 접합체는 다음의 영역 요소들 A-C, A-B-C, A-B-Y-C, A-Y-B-C 또는 A-Y-C로 구성될 수 있다. 일부 실시양태에서, 링커(영역 Y)는, 예를 들면, C6 내지 C12 아미노 알킬기를 포함한 C2 내지 C36 아미노 알킬기와 같은 아미노 알킬이다. 바람직한 실시양태에서, 링커(영역 Y)는 C6 아미노 알킬기이다.
대조군
용어 "대조군"은, 올리고뉴클레오티드의 효과 측정과 관련하여 사용될 때, 일반적으로 대조군은 비처리된 개체 또는 표적 세포, 또는 비-표적화 올리고뉴클레오티드(모조물)로 처리된 개체 또는 표적 세포인 것으로 이해된다. 그러나, 대조군은 또한 치료 표준으로 처리된 개체일 수 있다.
치료
본원에서 사용된 바와 같이 용어 "치료"는 기존 질환(예, 본원에서 언급되는 바와 같은 질환 또는 장애)의 치료, 또는 질환의 방지, 즉, 예방 둘 다를 말한다. 그러므로, 본원에 언급된 바와 같은 치료는, 일부 실시양태에서, 예방적일 수 있음을 인지할 것이다.
표적
본 발명의 한 양태는 돼지, 영장류 또는 인간 UBE3A 단백질 발현 수준을 조절하는 것, 특히 뉴런 세포, 특히 인간 뉴런 세포에서 부계 UBE3A 발현을 증가시키는 것이다. 인간 UBE3A 단백질은 유니프롯(Uniprot) nr. Q05086에 열거되어 있는 여러 이소폼들로 존재한다. 모계 UBE3A 유전자에서의 여러 돌연변이는 엔젤만 증후군을 야기할 수 있다.
본 발명의 올리고뉴클레오티드에 대한 표적 핵산은 RNA, 특히 긴 비-암호화 RNA이다. 본 발명의 올리고뉴클레오티드에 의해 표적화되는 긴 비-암호화 RNA는 인간 SNHG14(앙상블(Ensemble) 등록 번호 ENSG00000224078을 갖는 UBE3A-ATS, 버전 GRCh38.p2로도 알려져 있음)이다. 특히, 표적 핵산은 염색체 15 상의 위치 25278410 내지 25419462에 상응하는 SNORD109B의 하류의 영역(서열번호 1)이다. 붉은털 원숭이(마카카 뮬라타(Macaca mulatta))에서 UBE3A 억제유전자는 앙상블 어셈블리 MMUL 1.0을 사용하는 염색체 7 상의 위치 4222848 내지 4373084(정방향 가닥)에 상응하는 SNORD109A의 하류의 영역(서열번호 2)으로 정의된다.
일부 실시양태에서, 표적 핵산은 서열번호 1 또는 그의 천연 변이체이다.
특정 실시양태에서, 표적 핵산은 인간(서열번호 1)과 붉은털 원숭이(서열번호 2) 사이에서 보존되는 영역들에 상응한다. 특정 실시양태에서, 표적 핵산은 인간(서열번호 1), 붉은털 원숭이(서열번호 2) 및 마우스(서열번호 3) 사이에서 보존되는 영역들에 상응한다.
특정 실시양태에서, 표적 핵산은 UBE3A 전구체-mRNA에 대해 안티센스인 영역으로, 상기 영역은 서열번호 1의 위치 55319 내지 141053에 상응한다.
특정 실시양태에서, 표적 핵산은 SNORD109B의 하류 및 UBE3A 전구체-mRNA에 대한 안티센스인 영역의 상류인 영역으로, 상기 영역은 서열번호 1의 위치 1 내지 55319에 상응한다.
일부 실시양태에서, 표적 핵산은 시험관내 또는 생체내에서 세포, 예를 들면, 포유동물 세포, 특히 인간 세포(표적 세포)에 존재한다. 특정 실시양태에서, 표적 세포는 뉴런, 바람직하게는 인간 뉴런 세포이다.
표적 서열은 표적 핵산의 아서열일 수 있다. 일부 실시양태에서, 올리고뉴클레오티드는 UBE3A의 엑손9, 엑손10, 엑손13, 엑손14, 인트론14, 엑손15, 인트론15 및 엑손16의 안티센스 영역으로 이루어진 군에서 선택된 아서열을 표적화한다. 일부 실시양태에서, 올리고뉴클레오티드 또는 연속 뉴클레오티드 서열은, 서열번호 1의 위치 55319 내지 76274, 77483 내지 77573, 92157 내지 93403 및 97056 내지 97354로 이루어진 군에서 선택된 단일 가닥 핵산 분자와 하이브리드되거나 또는 상기 분자에 상보적이다. 일부 실시양태에서, 올리고뉴클레오티드 또는 연속 뉴클레오티드 서열은, 서열번호 1의 위치 60821 내지 60849, 77567 내지 77583, 92323 내지 92339 및 97156 내지 97172로 이루어진 군에서 선택된 단일 가닥 핵산 분자와 하이브리드되거나 또는 상기 분자에 상보적이다.
일부 실시양태에서, 표적 핵산은 서열번호 1의 위치 9200 내지 9250에 상응하는 영역이다.
일부 실시양태에서, 표적 핵산은 서열번호 1의 위치 11505 내지 11555에 상응하는 영역이다.
일부 실시양태에서, 표적 핵산은 서열번호 1의 위치 15100 내지 15150에 상응하는 영역이다.
일부 실시양태에서, 표적 핵산은 서열번호 1의 위치 30590 내지 30740에 상응하는 영역이다.
일부 실시양태에서, 표적 핵산은 서열번호 1의 위치 46380 내지 46430에 상응하는 영역이다.
본 발명의 올리고뉴클레오티드
본 발명은 부계 UBE3A의 발현을 조절할 수 있는, 특히 뉴런 세포에서 부계 발현된 UBE3A를 유도 또는 상향조절할 수 있는 올리고뉴클레오티드에 관한 것이다. 상기 조절은 SNORD109B의 하류의 긴 비-암호화 RNA SNHG14 전사체 상에 위치한 표적 핵산에 하이브리드화됨으로써 달성된다. 특정 실시양태에서, 본 발명의 올리고뉴클레오티드는 -10 kcal 미만의 ΔG°, 예를 들면, -10 내지 -60 kcal의 ΔG°, 예를 들어, -12 내지 -40 kacl, 예를 들어, -15 내지 -30 kcal 또는 -16 내지 -27 kcal, 예를 들어, -18 내지 -25 kcal의 ΔG°하에 서열번호 1의 표적 핵산의 아서열에 하이브리드화된다.
본 발명의 올리고뉴클레오티드는 SNORD109B의 하류의 돼지, 붉은털 원숭이 및/또는 인간 SNHG14 전사체를 표적화하는 안티센스 올리고뉴클레오티드이다.
일부 실시양태에서, 본 발명의 안티센스 올리고뉴클레오티드는 표적의 억제유전자를 제거하거나 저해하거나 감소시킴으로써 표적의 발현을 조절할 수 있다. 바람직하게, 본 발명의 올리고뉴클레오티드는 SNORD109B의 하류의 SNHG14 전사체의 분해 또는 제거에 의해, 세포에서 UBE3A 발현, 특히 뉴런에서 부계 UBE3A 발현을 유도한다. 일부 실시양태에서, 본 발명의 올리고뉴클레오티드는 UBE3A의 발현을, 식염수 또는 비-표적화 올리고뉴클레오티드로 처리된 뉴런 세포에서의 UBE3A의 발현 수준에 비해 20% 이상, 보다 바람직하게는 식염수 또는 비-표적화 올리고뉴클레오티드로 처리된 뉴런 세포에서의 UBE3A의 발현 수준에 비해 적어도 30%, 35%, 40%, 45%, 50%, 55%, 60%, 80%, 100%, 120%, 150%, 160%, 170%, 180%, 190%, 200%, 210%, 220%, 230%, 240% 또는 250% 만큼 증가시킬 수 있다. 또 다른 실시양태에서, 본 발명의 올리고뉴클레오티드는, SNORD115 수준을 식염수 또는 비-표적화 올리고뉴클레오티드로 처리된 세포에서의 SNORD115 수준에 비해 0%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 12%, 14%, 16%, 18%, 20%, 25% 또는 30%보다 많이 감소시키지 않으면서, SNORD109B의 하류의 SNHG14 전사체(특히 UBE3A 전구체-mRNA 영역에 대해 안티센스인 전사체 부분)의 수준을, 식염수 또는 비-표적화 올리고뉴클레오티드로 처리된 뉴런 세포에서의 SNORD109B의 하류의 SNHG14 전사체의 수준에 비해 20% 이상, 보다 바람직하게는 식염수 또는 비-표적화 올리고뉴클레오티드로 처리된 뉴런 세포에서의 SNORD109B의 하류의 SNHG14 전사체의 수준에 비해 적어도 30%, 40%, 50%, 60%, 70%, 80%, 90% 또는 95% 만큼 감소시킬 수 있다. SNRPN 및 SNORD116 전사체는 SNORD115 전사체로부터 상류에 위치하고, 결과적으로 SNORD115 전사체가 올리고뉴클레오티드에 의해 감소되지 않는 경우, SNRPN 및 SNORD116 전사체도 또한 감소되지 않을 가능성이 매우 높다. 또 다른 실시양태에서, SNRPN 및 SNORD116 전사체 수준은 식염수 또는 비-표적화 올리고뉴클레오티드로 처리된 세포에서의 SNRPN 및 SNORD116의 수준에 비해 0%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 12%, 14%, 16%, 18%, 20%, 25% 또는 30%보다 많이 감소되지 않는다.
표적 조절은 올리고뉴클레오티드의 연속 뉴클레오티드 서열과 표적 핵산 사이의 하이브리드화에 의해 촉발된다. 일부 실시양태에서, 본 발명의 올리고뉴클레오티드는 올리고뉴클레오티드와 표적 핵산 사이에 미스매치들을 포함한다. 미스매치들에도 불구하고, 표적 핵산에 대한 하이브리드화는 여전히 UBE3A 발현의 목적하는 조절을 나타내기에 충분할 수 있다. 미스매치로부터 비롯되는 감소된 결합 친화도는 유리하게, 올리고뉴클레오티드내 뉴클레오티드들의 증가된 수 및/또는 표적에 대한 결합 친화도를 증가시킬 수 있는 변형 뉴클레오시드, 예를 들면, 올리고뉴클레오티드 서열내에 존재하는, LNA를 포함한 2' 변형된 뉴클레오시드의 증가된 수에 의해 보상될 수 있다.
본 발명의 한 양태는 인간 염색체 15 상의 위치 25278410 내지 25419462에 90% 이상, 예를 들면, 95%, 예를 들어, 98%, 예를 들어, 100% 상보성을 갖는, 10 내지 30개 뉴클레오티드 길이의 연속 뉴클레오티드 서열을 포함하는 안티센스 올리고뉴클레오티드에 관한 것이다.
일부 실시양태에서, 올리고뉴클레오티드는, 서열번호 1, 2 또는 3으로 나타낸 표적 핵산의 영역과 90% 이상 상보적인, 예를 들면, 91% 이상, 예를 들면, 92% 이상, 예를 들면, 93% 이상, 예를 들면, 94% 이상, 예를 들면, 95% 이상, 예를 들면, 96% 이상, 예를 들면, 97% 이상, 예를 들면, 98% 이상, 또는 100% 상보적인 연속 서열을 포함한다.
바람직한 실시양태에서, 본 발명의 올리고뉴클레오티드 또는 그의 연속 뉴클레오티드 서열은 서열번호 1로 나타낸 표적 핵산의 영역에 완전히 상보적(100% 상보적)이거나, 또는 일부 실시양태에서는 올리고뉴클레오티드와 표적 핵산 사이에 1개 또는 2개의 미스매치를 포함할 수 있다.
일부 실시양태에서, 올리고뉴클레오티드 서열은 서열번호 1 및 서열번호 2에 존재하는 상응하는 표적 핵산 영역에 100% 상보적이다. 일부 실시양태에서, 올리고뉴클레오티드 서열은 서열번호 1, 2 및 3에 존재하는 상응하는 표적 핵산 영역에 100% 상보적이다.
일부 실시양태에서, 올리고뉴클레오티드는 서열번호 1에 존재하는 상응하는 표적 핵산 영역에 90% 이상 상보적, 예를 들면, 100% 상보적인, 10 내지 30개 뉴클레오티드 길이의 연속 뉴클레오티드 서열을 포함하며, 이때 상기 표적 핵산 영역은 표 1의 영역 A1 내지 A3649로 이루어진 군에서 선택된다.
[표 1]
본 발명의 올리고뉴클레오티드를 사용하여 표적화될 수 있는 서열번호 1의 영역들
Figure 112020127052610-pat00006
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Figure 112020127052610-pat00035
Figure 112020127052610-pat00036
일부 실시양태에서, 올리고뉴클레오티드는 서열번호 1에 존재하는 상응하는 표적 핵산 영역에 90% 이상 상보적, 예를 들면, 100% 상보적인, 10 내지 30개 뉴클레오티드 길이의 연속 뉴클레오티드 서열을 포함하며, 이때 상기 표적 핵산 영역은 표 2의 영역 B1 내지 B400으로 이루어진 군에서 선택된다.
[표 2]
본 발명의 올리고뉴클레오티드를 사용하여 표적화될 수 있는 서열번호 1의 영역들
Figure 112020127052610-pat00037
Figure 112020127052610-pat00038
Figure 112020127052610-pat00039
Figure 112020127052610-pat00040
특정 실시양태에서, 올리고뉴클레오티드 또는 연속 뉴클레오티드 서열은 표적 핵산의 한 영역(또는 아서열)에 상보적이며, 이때 상기 표적 핵산 영역은 서열번호 1의 위치 1589 내지 10889, 46089 내지 53989 및 60789 내지 62489로 이루어진 군에서 선택된다.
한 실시양태에서, 올리고뉴클레오티드는 서열번호 1의 위치 55319 내지 141053의 표적 핵산 서열에 90% 이상, 예를 들면, 100% 상보적인, 10 내지 30개 뉴클레오티드 길이의 연속 뉴클레오티드 서열을 포함한다.
한 실시양태에서, 올리고뉴클레오티드는 서열번호 1의 위치 1 내지 55318의 표적 핵산 서열에 90% 이상, 예를 들면, 100% 상보적인, 10 내지 30개 뉴클레오티드 길이의 연속 뉴클레오티드 서열을 포함한다.
일부 실시양태에서, 올리고뉴클레오티드는 서열번호 1의 위치 55319 내지 76274, 77483 내지 77573, 92157 내지 93403 및 97056 내지 97354에 상응하는 군에서 선택된 표적 핵산의 아서열에 90% 이상 상보적인, 10 내지 30개 뉴클레오티드 길이의 연속 뉴클레오티드 서열을 포함한다.
일부 실시양태에서, 올리고뉴클레오티드는 서열번호 1의 위치 60821 내지 60849, 77567 내지 77583, 92323 내지 92339 및 97156 내지 97172에 상응하는 군에서 선택된 표적 핵산의 아서열에 90% 이상 상보적인, 10 내지 30개 뉴클레오티드 길이의 연속 뉴클레오티드 서열을 포함한다.
일부 실시양태에서, 올리고뉴클레오티드는 서열번호 1의 위치 5218 내지 5240에 상응하는 표적 핵산의 아서열에 90% 이상 상보적인, 10 내지 30개 뉴클레오티드 길이의 연속 뉴클레오티드 서열을 포함한다.
일부 실시양태에서, 올리고뉴클레오티드는 서열번호 1의 위치 5782-5803에 상응하는 표적 핵산의 아서열에 90% 이상 상보적인, 10 내지 30개 뉴클레오티드 길이의 연속 뉴클레오티드 서열을 포함한다.
일부 실시양태에서, 올리고뉴클레오티드는 서열번호 1의 위치 8113 내지 8139에 상응하는 표적 핵산의 아서열에 90% 이상 상보적인, 10 내지 30개 뉴클레오티드 길이의 연속 뉴클레오티드 서열을 포함한다.
일부 실시양태에서, 올리고뉴클레오티드는 서열번호 1의 위치 9200 내지 9250에 상응하는 표적 핵산의 아서열에 90% 이상 상보적인, 10 내지 30개 뉴클레오티드 길이의 연속 뉴클레오티드 서열을 포함한다.
일부 실시양태에서, 올리고뉴클레오티드는 서열번호 1의 위치 11505 내지 11555에 상응하는 표적 핵산의 아서열에 90% 이상 상보적인, 10 내지 30개 뉴클레오티드 길이의 연속 뉴클레오티드 서열을 포함한다.
일부 실시양태에서, 올리고뉴클레오티드는 서열번호 1의 위치 13223 내지 13242에 상응하는 표적 핵산의 아서열에 90% 이상 상보적인, 10 내지 30개 뉴클레오티드 길이의 연속 뉴클레오티드 서열을 포함한다.
일부 실시양태에서, 올리고뉴클레오티드는 서열번호 1의 위치 15100 내지 15150에 상응하는 표적 핵산의 아서열에 90% 이상 상보적인, 10 내지 30개 뉴클레오티드 길이의 연속 뉴클레오티드 서열을 포함한다.
일부 실시양태에서, 올리고뉴클레오티드는 서열번호 1의 위치 15113 내지 15180에 상응하는 표적 핵산의 아서열에 90% 이상 상보적인, 10 내지 30개 뉴클레오티드 길이의 연속 뉴클레오티드 서열을 포함한다.
일부 실시양태에서, 올리고뉴클레오티드는 서열번호 1의 위치 29635 내지 29705에 상응하는 표적 핵산의 아서열에 90% 이상 상보적인, 10 내지 30개 뉴클레오티드 길이의 연속 뉴클레오티드 서열을 포함한다.
일부 실시양태에서, 올리고뉴클레오티드는 서열번호 1의 위치 30590 내지 30740에 상응하는 표적 핵산의 아서열에 90% 이상 상보적인, 10 내지 30개 뉴클레오티드 길이의 연속 뉴클레오티드 서열을 포함한다.
일부 실시양태에서, 올리고뉴클레오티드는 서열번호 1의 위치 39800 내지 39855에 상응하는 표적 핵산의 아서열에 90% 이상 상보적인, 10 내지 30개 뉴클레오티드 길이의 연속 뉴클레오티드 서열을 포함한다.
일부 실시양태에서, 올리고뉴클레오티드는 서열번호 1의 위치 44435 내지 44460에 상응하는 표적 핵산의 아서열에 90% 이상 상보적인, 10 내지 30개 뉴클레오티드 길이의 연속 뉴클레오티드 서열을 포함한다.
일부 실시양태에서, 올리고뉴클레오티드는 서열번호 1의 위치 45245 내지 45270에 상응하는 표적 핵산의 아서열에 90% 이상 상보적인, 10 내지 30개 뉴클레오티드 길이의 연속 뉴클레오티드 서열을 포함한다.
일부 실시양태에서, 올리고뉴클레오티드는 서열번호 1의 위치 46380 내지 46430에 상응하는 표적 핵산의 아서열에 90% 이상 상보적인, 10 내지 30개 뉴클레오티드 길이의 연속 뉴클레오티드 서열을 포함한다.
일부 실시양태에서, 올리고뉴클레오티드는 서열번호 1의 위치 68915 내지 68940에 상응하는 표적 핵산의 아서열에 90% 이상 상보적인, 10 내지 30개 뉴클레오티드 길이의 연속 뉴클레오티드 서열을 포함한다.
일부 실시양태에서, 올리고뉴클레오티드는 길이에 있어서 8 내지 35개 뉴클레오티드, 예를 들면, 길이에 있어서 10 내지 30개, 예를 들어, 11 내지 22개, 예를 들어, 12 내지 18개, 예를 들어, 13 내지 17개 또는 14 내지 16개 연속 뉴클레오티드를 포함하거나 그로 이루어진다.
일부 실시양태에서, 올리고뉴클레오티드 또는 그의 연속 뉴클레오티드 서열은 22개 이하의 뉴클레오티드, 예를 들면, 20개 이하의 뉴클레오티드, 예를 들어, 18개 이하의 뉴클레오티드, 예를 들어, 14, 15, 16 또는 17개 뉴클레오티드를 포함하거나 그로 이루어진다. 본원에 제공된 임의의 범위는 그 범위 종말점들을 포함하는 것으로 이해해야 한다. 따라서, 올리고뉴클레오티드가 10 내지 30개의 뉴클레오티드를 포함한다고 하면, 10개 및 30개 뉴클레오티드가 둘 다 포함된다.
일부 실시양태에서, 연속 뉴클레오티드 서열은 길이에 있어서 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29 또는 30개의 연속 뉴클레오티드를 포함하거나 그로 이루어진다. 바람직한 실시양태에서, 올리고뉴클레오티드는 길이에 있어서, 16, 17, 18 또는 19개 뉴클레오티드를 포함하거나 그로 이루어진다.
일부 실시양태에서, 안티센스 올리고뉴클레오티드 또는 연속 뉴클레오티드 서열은, 길이에 있어서, 서열번호 4 내지 150으로 이루어진 군에서 선택된 서열에 대해 90% 이상의 동일성, 바람직하게는 100% 동일성을 갖는, 10 내지 30개의 뉴클레오티드를 포함하거나 그로 이루어진다(실시예 부분에서 표 3에 열거된 모티프 서열 참조).
일부 실시양태에서, 안티센스 올리고뉴클레오티드 또는 연속 뉴클레오티드 서열은, 길이에 있어서, 서열번호 4 내지 818로 이루어진 군에서 선택된 서열에 대해 90% 이상의 동일성, 바람직하게는 100% 동일성을 갖는, 10 내지 30개의 뉴클레오티드를 포함하거나 그로 이루어진다(실시예 부분에서 표 3에 열거된 모티프 서열 참조).
일부 실시양태에서, 안티센스 올리고뉴클레오티드 또는 연속 뉴클레오티드 서열은, 길이에 있어서, 서열번호 4 내지 678로 이루어진 군에서 선택된 서열에 대해 90% 이상의 동일성, 바람직하게는 100% 동일성을 갖는, 10 내지 30개의 뉴클레오티드를 포함하거나 그로 이루어진다(실시예 부분에서 표 3에 열거된 모티프 서열 참조).
일부 실시양태에서, 안티센스 올리고뉴클레오티드 또는 연속 뉴클레오티드 서열은, 길이에 있어서, 서열번호 166, 167, 167 또는 169로 이루어진 군에서 선택된 서열에 대해 90% 이상의 동일성, 바람직하게는 100% 동일성을 갖는, 10 내지 30개의 뉴클레오티드를 포함하거나 그로 이루어진다(실시예 부분에서 표 3에 열거된 모티프 서열 참조).
일부 실시양태에서, 안티센스 올리고뉴클레오티드 또는 연속 뉴클레오티드 서열은, 길이에 있어서, 서열번호 570, 571 ,572, 679, 680, 681, 682 및 683으로 이루어진 군에서 선택된 서열에 대해 90% 이상의 동일성, 바람직하게는 100% 동일성을 갖는, 10 내지 30개의 뉴클레오티드를 포함하거나 그로 이루어진다(실시예 부분에서 표 3에 열거된 모티프 서열 참조).
일부 실시양태에서, 안티센스 올리고뉴클레오티드 또는 연속 뉴클레오티드 서열은, 길이에 있어서, 서열번호 34, 186, 187, 188, 573, 574, 575, 576, 572, 684, 685, 686, 687, 688, 689, 690, 691, 692, 963, 964, 965 및 696으로 이루어진 군에서 선택된 서열에 대해 90% 이상의 동일성, 바람직하게는 100% 동일성을 갖는, 10 내지 30개의 뉴클레오티드를 포함하거나 그로 이루어진다(실시예 부분에서 표 3에 열거된 모티프 서열 참조).
일부 실시양태에서, 안티센스 올리고뉴클레오티드 또는 연속 뉴클레오티드 서열은, 길이에 있어서, 서열번호 35, 199, 200, 201, 202, 203, 204, 205, 206, 207, 209 및 210 또는 서열번호 582, 583 및 584로 이루어진 군에서 선택된 서열에 대해 90% 이상의 동일성, 바람직하게는 100% 동일성을 갖는, 10 내지 30개의 뉴클레오티드를 포함하거나 그로 이루어진다(실시예 부분에서 표 3에 열거된 모티프 서열 참조).
일부 실시양태에서, 안티센스 올리고뉴클레오티드 또는 연속 뉴클레오티드 서열은, 길이에 있어서, 서열번호 221, 222, 223, 224, 225, 585, 586, 587, 588, 589, 698, 699,700, 701, 702, 703, 704, 705, 706, 707, 708, 709, 710, 711, 712, 713, 714, 715, 716, 717 및 718로 이루어진 군에서 선택된 서열에 대해 90% 이상의 동일성, 바람직하게는 100% 동일성을 갖는, 10 내지 30개의 뉴클레오티드를 포함하거나 그로 이루어진다(실시예 부분에서 표 3에 열거된 모티프 서열 참조).
일부 실시양태에서, 안티센스 올리고뉴클레오티드 또는 연속 뉴클레오티드 서열은, 길이에 있어서, 서열번호 236, 237, 238, 239, 240 및 590으로 이루어진 군에서 선택된 서열에 대해 90% 이상의 동일성, 바람직하게는 100% 동일성을 갖는, 10 내지 30개의 뉴클레오티드를 포함하거나 그로 이루어진다(실시예 부분에서 표 3에 열거된 모티프 서열 참조).
일부 실시양태에서, 안티센스 올리고뉴클레오티드 또는 연속 뉴클레오티드 서열은, 길이에 있어서, 서열번호 241, 591 및 719로 이루어진 군에서 선택된 서열에 대해 90% 이상의 동일성, 바람직하게는 100% 동일성을 갖는, 10 내지 30개의 뉴클레오티드를 포함하거나 그로 이루어진다(실시예 부분에서 표 3에 열거된 모티프 서열 참조).
일부 실시양태에서, 안티센스 올리고뉴클레오티드 또는 연속 뉴클레오티드 서열은, 길이에 있어서, 서열번호 46, 47,48, 285, 286, 287, 288, 289, 290, 291, 292, 293, 294, 295, 296, 297, 298, 299, 300, 301, 302, 303, 304,305, 613, 614, 615, 616, 617, 618, 619, 620, 621, 622, 623, 624, 625, 626,627, 628, 629, 630, 631, 632, 721, 722, 723, 724, 725, 726, 727, 728, 729, 730, 731, 732, 734, 735, 736, 737, 738, 739, 740, 741, 742, 743, 744, 745, 746, 747, 748, 749, 750, 751, 752, 753, 754, 755, 756, 757, 758, 759, 760, 761, 762, 763, 764, 765, 766, 767, 768, 769, 770, 771, 772, 773, 774, 775, 776, 777, 778, 779, 780, 781, 782, 783, 784, 785, 786, 787, 788, 789, 790, 791, 792, 793, 794, 795, 796, 797, 798, 799, 800, 800, 800, 800, 800, 801, 801, 802, 803, 804, 805, 806 및 807로 이루어진 군에서 선택된 서열에 대해 90% 이상의 동일성, 바람직하게는 100% 동일성을 갖는, 10 내지 30개의 뉴클레오티드를 포함하거나 그로 이루어진다(실시예 부분에서 표 3에 열거된 모티프 서열 참조).
일부 실시양태에서, 안티센스 올리고뉴클레오티드 또는 연속 뉴클레오티드 서열은, 길이에 있어서, 서열번호 331, 332, 638, 639, 640, 808, 809, 810, 811, 812, 813, 814 및 815로 이루어진 군에서 선택된 서열에 대해 90% 이상의 동일성, 바람직하게는 100% 동일성을 갖는, 10 내지 30개의 뉴클레오티드를 포함하거나 그로 이루어진다(실시예 부분에서 표 3에 열거된 모티프 서열 참조).
일부 실시양태에서, 안티센스 올리고뉴클레오티드 또는 연속 뉴클레오티드 서열은, 길이에 있어서, 서열번호 409, 410, 411, 642, 643, 644, 645, 646, 816, 818 및 818로 이루어진 군에서 선택된 서열에 대해 90% 이상의 동일성, 바람직하게는 100% 동일성을 갖는, 10 내지 30개의 뉴클레오티드를 포함하거나 그로 이루어진다(실시예 부분에서 표 3에 열거된 모티프 서열 참조).
연속 핵염기 서열(모티프 서열)은, 예를 들면, 뉴클레아제 내성 및/또는 표적 핵산에 대한 결합 친화도를 증가시키도록 변형될 수 있는 것으로 이해된다. 변형은 정의에서 및 "올리고뉴클레오티드 디자인" 부분에서 기술되어 있다. 표 3은 각 모티프 서열의 바람직한 디자인들을 열거하고 있다.
올리고뉴클레오티드 디자인
올리고뉴클레오티드 디자인은 올리고뉴클레오티드 서열에서 뉴클레오시드 당 변형의 패턴을 말한다. 본 발명의 올리고뉴클레오티드는 당-변형된 뉴클레오시드를 포함하며 또한 DNA 또는 RNA 뉴클레오시드를 포함할 수 있다. 일부 실시양태에서, 올리고뉴클레오티드는 당-변형된 뉴클레오시드 및 DNA 뉴클레오시드를 포함한다. 본 발명의 올리고뉴클레오티드 내에 변형된 뉴클레오시드의 혼입은 표적 핵산에 대한 올리고뉴클레오티드의 친화도를 증대시킬 수 있다. 그러한 경우, 변형된 뉴클레오시드는 친화도 증대 변형 뉴클레오시드로 지칭될 수 있다.
한 실시양태에서, 올리고뉴클레오티드는 1개 이상의 변형 뉴클레오시드, 예를 들면, 2개 이상, 3개 이상, 4개 이상, 5개 이상, 6개 이상, 7개 이상, 8개 이상, 9개 이상, 10개 이상, 11개 이상, 12개 이상, 13개 이상, 14개 이상, 15개 이상 또는 16개 이상의 변형 뉴클레오시드를 포함한다. 한 실시양태에서, 올리고뉴클레오티드는 1 내지 10개의 변형 뉴클레오시드, 예를 들면, 2 내지 9개의 변형 뉴클레오시드, 예를 들면, 3 내지 8개의 변형 뉴클레오시드, 예를 들어, 4 내지 7개의 변형 뉴클레오시드, 예를 들어, 6 또는 7개의 변형 뉴클레오시드를 포함한다. 일부 실시양태에서, 변형 뉴클레오시드들 중 1개 이상은 잠금 핵산(LNA)이다, 예를 들면, 변형 뉴클레오시드들 중 2개 이상, 예를 들어, 3개 이상, 4개 이상, 5개 이상, 6개 이상, 7개 이상 또는 8개 이상이 LNA이다. 또 다른 실시양태에서, 모든 변형 뉴클레오시드들이 LNA이다.
한 실시양태에서, 본 발명의 올리고뉴클레오티드는 상기 3가지 유형의 변형(변형된 당, 변형된 핵염기 및 변형된 뉴클레오시드간 결합) 또는 그의 조합으로부터 독립적으로 선택된 변형을 포함할 수 있다. 바람직하게, 올리고뉴클레오티드는 1개 이상의 당 변형된 뉴클레오시드, 예를 들면, 2' 당 변형된 뉴클레오시드를 포함한다. 바람직하게, 본 발명의 올리고뉴클레오티드는 2'-O-알킬-RNA, 2'-O-메틸-RNA, 2'-알콕시-RNA, 2'-O-메톡시에틸-RNA, 2'-아미노-DNA, 2'-플루오로-DNA, 아라비노 핵산(ANA), 2'-플루오로-ANA 및 LNA 뉴클레오시드로 이루어진 군에서 독립적으로 선택된 2' 당 변형된 뉴클레오시드를 1개 이상 포함한다. 보다 더 바람직하게는 상기 1개 이상의 변형 뉴클레오시드는 LNA이다.
또 다른 실시양태에서, 올리고뉴클레오티드는 1개 이상의 변형된 뉴클레오시드간 결합을 포함한다. 바람직한 실시양태에서, 연속 뉴클레오티드 서열내 뉴클레오시드간 결합은 포스포로티오에이트 또는 보라노포스페이트 뉴클레오시드간 결합이다.
일부 실시양태에서, 본 발명의 올리고뉴클레오티드는 2'-MOE-RNA인 변형 뉴클레오시드를 1개 이상, 예를 들면, 2, 3, 4, 5, 6, 7, 8, 9 또는 10개의 2'-MOE-RNA 뉴클레오시드 단위를 포함한다. 일부 실시양태에서, 상기 변형 뉴클레오시드들 중 1개 이상은 2'-플루오로 DNA, 예를 들면, 2, 3, 4, 5, 6, 7, 8, 9 또는 10개의 2'-플루오로-DNA 뉴클레오시드 단위이다.
일부 실시양태에서, 본 발명의 올리고뉴클레오티드는 1개 이상의 LNA 단위, 예를 들면, 1, 2, 3, 4, 5, 6, 7 또는 8개의 LNA 단위, 예를 들어, 2 내지 6개 LNA 단위, 예를 들어, 3 내지 7개 LNA 단위, 4 내지 8개 LNA 단위, 또는 3, 4, 5, 6 또는 7개의 LNA 단위를 포함한다. 일부 실시양태에서, 모든 변형 뉴클레오시드들은 LNA 뉴클레오시드이다. 또 다른 실시양태에서, 올리고뉴클레오티드는 베타-D-옥시-LNA, 및 베타-D 또는 알파-L 입체형태중 어느 하나의 하기 LNA 단위들: 티오-LNA, 아미노-LNA, 옥시-LNA, 및/또는 ENA 또는 그의 조합 중 하나 이상을 둘 다 포함할 수 있다. 또 다른 실시양태에서, 모든 LNA 시토신 단위는 5-메틸-시토신이다. 바람직한 실시양태에서, 올리고뉴클레오티드 또는 연속 뉴클레오티드 서열은 뉴클레오티드 서열의 5' 말단에 1개 이상의 LNA 단위 및 3' 말단에 2개 이상의 LNA 단위를 갖는다.
일부 실시양태에서, 본 발명의 올리고뉴클레오티드는 1개 이상의 LNA 단위 및 1개 이상의 2' 치환된 변형 뉴클레오시드를 포함한다.
본 발명의 일부 실시양태에서, 올리고뉴클레오티드는 2' 당 변형된 뉴클레오시드 및 DNA 단위 둘 다를 포함한다. 바람직하게, 올리고뉴클레오티드는 LNA 및 DNA 단위 둘 다를 포함한다. 바람직하게, LNA와 DNA 단위의 합한 총수는 8 내지 30개, 예를 들면, 10 내지 25개, 바람직하게는 12 내지 22개, 예를 들면, 12 내지 18개, 보다 더 바람직하게는 11 내지 16개이다. 본 발명의 일부 실시양태에서, 올리고뉴클레오티드의 뉴클레오티드 서열, 예를 들면, 연속 뉴클레오티드 서열은 적어도 1개 또는 2개의 LNA 단위로 이루어지고, 나머지 뉴클레오티드 단위는 DNA 단위이다. 일부 실시양태에서, 올리고뉴클레오티드는, 선택적으로 포스포로티오에이트와 같은 변형된 뉴클레오시드간 결합과 함께, LNA 뉴클레오시드들 및 천연 뉴클레오시드들(예를 들면, RNA 또는 DNA, 가장 바람직하게는 DNA 뉴클레오시드) 만을 포함한다.
본 발명의 한 실시양태에서, 본 발명의 올리고뉴클레오티드는 RNase H를 구성할 수 있다.
갭머 디자인
바람직한 실시양태에서, 본 발명의 올리고뉴클레오티드는 본원에서 "갭머"로만도 지칭되는 갭머 디자인 또는 구조를 갖는다. 갭머 구조에서, 올리고뉴클레오티드는 3개 이상의 별개의 구조적 영역들, 5'-측면서열, 갭 및 3'-측면서열, F-G-F'를 5' → 3' 방향으로 포함한다. 상기 디자인에서, 측부 영역 F 및 F'(날개서열 영역으로도 지칭됨)는 UBE3A 표적 핵산에 상보적인 변형 뉴클레오시드의 연속 신장서열을 포함하는 반면, 갭 영역 G는, 올리고뉴클레오티드가 표적 핵산과 이중체로 존재하는 경우, 뉴클레아제, 바람직하게는 RNase, 예를 들면, RNase H와 같은 엔도뉴클레아제를 구성할 수 있는 뉴클레오티드의 연속 신장서열을 포함한다. 뉴클레아제, 특히 RNase H를 구성할 수 있는 뉴클레오시드는 DNA, 알파-L-옥시-LNA, 2'-플루오로-ANA 및 UNA로 이루어진 군에서 선택될 수 있다. 영역 G의 5' 및 3' 말단 측면에 위치한 영역 F 및 F'는 바람직하게는 비-뉴클레아제 구성 뉴클레오시드(3' 엔도(endo) 구조를 갖는 뉴클레오시드), 보다 바람직하게는 하나 이상의 친화도 증대 변형 뉴클레오시드를 포함한다. 일부 실시양태에서, 3' 측면서열은 1개 이상의 LNA 뉴클레오시드, 바람직하게는 2개 이상의 LNA 뉴클레오시드를 포함한다. 일부 실시양태에서, 5' 측면서열은 1개 이상의 LNA 뉴클레오시드를 포함한다. 일부 실시양태에서, 5' 및 3' 측부 영역은 둘 다 LNA 뉴클레오시드를 포함한다. 일부 실시양태에서, 측부 영역중 모든 뉴클레오시드는 LNA 뉴클레오시드이다. 다른 실시양태에서, 측부 영역들은 LNA 뉴클레오시드 및 다른 뉴클레오시드(혼합 측면서열), 예를 들면, DNA 뉴클레오시드 및/또는 비-LNA 변형 뉴클레오시드, 예를 들어, 2' 치환된 뉴클레오시드를 둘 다 포함할 수 있다. 이 경우, 갭은 친화도 증대 변형 뉴클레오시드, 바람직하게는 LNA, 예를 들어, 베타-D-옥시-LNA가 5' 및 3' 말단 측면에 위치한 5개 이상의 RNase H 구성 뉴클레오시드(2' 엔도 구조를 갖는 뉴클레오시드, 바람직하게는 DNA)의 연속 서열로서 정의된다. 결과적으로, 갭 영역에 인접한 5' 측부 영역 및 3' 측부 영역의 뉴클레오시드들은 변형된 뉴클레오시드, 바람직하게는 비-뉴클레아제 구성 뉴클레오시드이다. 측면서열이 DNA를 포함하는 혼합 측면서열들을 갖는 올리고뉴클레오티드에서 5' 및 3' 뉴클레오시드는 변형 뉴클레오시드이다.
영역 F
영역 G의 5' 말단에 결합된 영역 F(5' 측면서열 또는 5' 날개서열)는 1개 이상의 변형 뉴클레오시드, 예를 들면, 2개 이상, 3개 이상, 4개 이상, 5개 이상, 6개 이상, 7개 이상의 변형 뉴클레오시드를 포함하거나, 함유하거나 또는 그로 이루어진다. 한 실시양태에서, 영역 F는 1 내지 7개의 변형 뉴클레오시드, 예를 들면, 2 내지 6개의 변형 뉴클레오시드, 예를 들면, 2 내지 5개의 변형 뉴클레오시드, 예를 들어, 2 내지 4개의 변형 뉴클레오시드, 예를 들어, 1 내지 3개의 변형 뉴클레오시드, 예를 들어, 1, 2, 3 또는 4개의 변형 뉴클레오시드를 포함하거나 그로 이루어진다. 또 다른 실시양태에서, 또 다른 추가의 뉴클레오시드가 영역 F의 5' 말단에 결합되어, 바람직하게는 1, 2 또는 3개의 뉴클레오시드 단위, 예를 들면, DNA 뉴클레오시드를 포함하는 영역 D를 나타낼 수 있다. 영역 D는 "링커"의 정의에서 기술된 생체절단성 (B) 링커의 기능을 가질 수 있다.
일부 실시양태에서, 영역 F내의 변형 뉴클레오시드는 3' 엔도 구조를 갖는다.
한 실시양태에서, 영역 F내의 변형 뉴클레오시드중 1개 이상은 2' 변형된 뉴클레오시드이다.
또 다른 실시양태에서, 영역 F내의 2' 변형 뉴클레오시드중 1개 이상은 2'-O-알킬-RNA 단위, 2'-O-메틸-RNA, 2'-아미노-DNA 단위, 2'-플루오로-DNA 단위, 2'-알콕시-RNA, MOE 단위, LNA 단위, 아라비노 핵산(ANA) 단위 및 2'-플루오로-ANA 단위로부터 선택된다.
본 발명의 한 실시양태에서, 영역 F 내의 모든 변형 뉴클레오시드는 LNA 뉴클레오시드이다. 또 다른 실시양태에서, 영역 F 내의 LNA 뉴클레오시드는, 베타-D 또는 알파-L 입체형태중 어느 하나의 옥시-LNA, 티오-LNA, 아미노-LNA, cET 및/또는 ENA, 또는 그의 조합으로 이루어진 군에서 독립적으로 선택된다. 바람직한 실시양태에서, 영역 F는 연속 서열의 5' 말단에 1개 이상의 베타-D-옥시 LNA 단위를 갖는다.
영역 G
영역 G(갭 영역)는 바람직하게는 전술한 뉴클레아제, 특히 RNaseH를 구성할 수 있는 연속 뉴클레오시드를 4개 이상, 예를 들면, 5개 이상, 예를 들면, 6개 이상, 7개 이상, 8개 이상, 9개 이상, 10개 이상, 11개 이상, 12개 이상, 13개 이상, 14개 이상, 15개 이상, 또는 16개 이상 포함하거나 함유하거나 또는 그로 이루어진다. 또 다른 실시양태에서, 영역 G는 전술한 뉴클레아제를 구성할 수 있는 연속 뉴클레오티드 단위를 5 내지 12개, 또는 6 내지 10개, 또는 7 내지 9개, 예를 들면 8개 포함하거나 함유하거나 또는 그로 이루어진다.
뉴클레아제를 구성할 수 있는, 영역 G내의 뉴클레오시드 단위는, 한 실시양태에서, DNA, 알파-L-LNA, C4' 알킬화 DNA(둘 다 본원에 참고로 도입되는 PCT/EP2009/050349 호 및 문헌 [Vester et al., Bioorg. Med. Chem. Lett. 18 (2008) 2296 - 2300]에 기술된 바와 같은), ANA 및 2'F-ANA[Mangos et al. 2003 J. AM. CHEM. SOC. 125, 654-661]와 같은 아라비노스 유래 뉴클레오시드, UNA(잠금해제 핵산)(본원에 참고로 도입되는 문헌 [Fluiter et al., Mol. Biosyst., 2009, 10, 1039]에 기술된 바와 같은)로 이루어진 군에서 선택된다. UNA는, 전형적으로 리보스의 C2와 C3 사이의 결합이 제거되어 잠금해제된 "당" 잔기를 형성하는 잠금해제 핵산이다.
또 다른 실시양태에서, 영역 G내의 1개 이상의 뉴클레오시드는 DNA 뉴클레오시드 단위, 예를 들면, 1 내지 16개 DNA 단위, 예를 들면, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 또는 15개 DNA 단위, 바람직하게는 2 내지 13개 DNA 단위, 예를 들어, 4 내지 12개 DNA 단위, 보다 바람직하게는 5 내지 11개, 또는 10 내지 16개, 11 내지 15개 또는 12 내지 14개 DNA 단위이다. 일부 실시양태에서, 영역 G는 100% DNA 단위로 이루어진다. 바람직한 실시양태에서, G는, 가장 바람직하게는 10, 11, 12, 13, 14 또는 15개 DNA 단위로 이루어진다.
또 다른 실시양태에서, 영역 G는 DNA와, RNase H 절단을 매개할 수 있는 다른 뉴클레오시드의 혼합물로 이루어질 수 있다. 영역 G는 50% 이상의 DNA, 보다 바람직하게는 60%, 70% 또는 80% DNA, 및 보다 더 바람직하게는 90% 또는 95% DNA로 이루어질 수 있다.
또 다른 실시양태에서, 영역 G내의 1개 이상의 뉴클레오시드 단위는 알파-L-LNA 뉴클레오시드 단위, 예를 들면, 1개 이상의 알파-L-LNA 단위, 예를 들어, 2, 3, 4, 5, 6, 7, 8 또는 9개 알파-L-LNA 단위이다. 또 다른 실시양태에서, 영역 G는 알파-L-옥시-LNA 단위인 알파-L-LNA 단위를 1개 이상 포함한다. 또 다른 실시양태에서, 영역 G는 DNA와 알파-L-LNA 뉴클레오시드 단위의 조합을 포함한다.
일부 실시양태에서, 영역 G내의 연속 서열의 크기는 더 길 수 있다, 예를 들면, 15, 16, 17, 18, 19 또는 20개 뉴클레오시드 단위일 수 있다.
일부 실시양태에서, 영역 G내의 뉴클레오시드는 2' 엔도 구조를 갖는다.
영역 F'
영역 G의 3' 말단에 결합된 영역 F'(3' 측면서열 또는 3' 날개서열)는 1개 이상의 변형 뉴클레오시드, 예를 들면, 2개 이상, 3개 이상, 4개 이상, 5개 이상, 6개 이상, 7개 이상의 변형 뉴클레오시드를 포함하거나 함유하거나 또는 그로 이루어진다. 한 실시양태에서, 영역 F'는 1 내지 7개의 변형 뉴클레오시드, 예를 들면, 2 내지 6개의 변형 뉴클레오시드, 예를 들면, 2 내지 4개의 변형 뉴클레오시드, 예를 들어, 1 내지 3개의 변형 뉴클레오시드, 예를 들어, 1, 2, 3 또는 4개의 변형 뉴클레오시드를 포함하거나 그로 이루어진다. 또 다른 실시양태에서, 또 다른 추가의 뉴클레오시드가 영역 F'의 3' 말단에 결합되어, 바람직하게는 1, 2 또는 3개의 뉴클레오시드 단위, 예를 들면, DNA 뉴클레오시드를 포함하는 영역 D'를 나타낸다. 영역 D'는 "링커" 부분에서 기술된 생체절단성 (B) 링커의 기능을 가질 수 있다.
일부 실시양태에서, 영역 F'내의 변형 뉴클레오시드는 3' 엔도 구조를 갖는다.
바람직한 실시양태에서, 영역 F'내의 변형 뉴클레오시드는 LNA이다.
또 다른 실시양태에서, 영역 F'내의 변형 뉴클레오시드는 2'-O-알킬-RNA 단위, 2'-O-메틸-RNA, 2'-아미노-DNA 단위, 2'-플루오로-DNA 단위, 2'-알콕시-RNA, MOE 단위, LNA 단위, 아라비노 핵산(ANA) 단위 및 2'-플루오로-ANA 단위로부터 선택된다.
본 발명의 한 실시양태에서, 영역 F' 내의 모든 변형 뉴클레오시드는 LNA 뉴클레오시드이다. 또 다른 실시양태에서, 영역 F' 내의 LNA 뉴클레오시드는, 베타-D 또는 알파-L 입체형태중 어느 하나의 옥시-LNA, 티오-LNA, 아미노-LNA, cET 및/또는 ENA, 또는 그의 조합으로 이루어진 군에서 독립적으로 선택된다. 바람직한 실시양태에서, 영역 F'는 연속 서열의 3' 말단에 2개 이상의 베타-D-옥시 LNA 단위를 갖는다.
영역 D 및 D'
영역 D 및 D'는 각각 영역 F의 5' 말단 또는 영역 F'의 3' 말단에 결합될 수 있다.
영역 D 또는 D'는 독립적으로, 표적 핵산에 상보적이거나 비-상보적일 수 있는, 1, 2, 3, 4 또는 5개의 추가 뉴클레오티드를 포함할 수 있다. 이와 관련하여, 본 발명의 올리고뉴클레오티드는, 일부 실시양태에서, 또 다른 뉴클레오티드가 5' 및/또는 3' 말단의 측면에 위치한 표적을 조절할 수 있는 연속 뉴클레오티드 서열을 포함할 수 있다. 상기 추가의 뉴클레오티드는 뉴클레아제 민감성 생체절단성 링커(링커의 정의 참조)로 작용할 수 있다. 일부 실시양태에서, 추가의 5' 및/또는 3' 말단 뉴클레오티드는 포스포다이에스터 결합에 의해 연결되고, DNA 또는 RNA일 수 있다. 또 다른 실시양태에서, 추가의 5' 및/또는 3' 말단 뉴클레오티드는, 예를 들면, 뉴클레아제 안정성을 증대시키기 위해 또는 합성의 용이성을 위해 포함될 수 있는 변형 뉴클레오티드이다. 한 실시양태에서, 본 발명의 올리고뉴클레오티드는 연속 뉴클레오티드 서열 이외에 영역 D 및/또는 D'를 포함한다.
본 발명의 갭머 올리고뉴클레오티드는 하기 식으로 나타낼 수 있다:
F-G-F'; 특히 F1-7-G4-12-F'1-7
D-F-G-F', 특히 D1-3-F1-7-G4-12-F'1-7
F-G-F'-D', 특히 F1-7-G4-12-F'1-7-D'1-3
D-F-G-F'-D', 특히 D1-3-F1-7-G4-12-F'1-7-D'1-3
영역 F, G 및 F', D 및 D' 내의 뉴클레오시드들의 바람직한 수 및 유형은 전술하였다. 개개 올리고뉴클레오티드의 디자인은 또한 UBE3A의 발현을 조절하기 위해 사용시 올리고뉴클레오티드의 성질에 큰 영향을 미칠 수 있다.
일부 실시양태에서, 올리고뉴클레오티드는 길이에 있어서 14, 15, 16, 17, 18, 19 또는 20개 뉴클레오티드로 이루어진 갭머이며, 상기 갭머에서 영역 F 및 F'는 각각 독립적으로, UBE3A 전구체-mRNA(표적 핵산)에 대해 안티센스인 인간 SNHG14 긴 비-암호화 RNA의 일부에 상보적인 변형 뉴클레오시드 단위 2, 3 또는 4개로 이루어지고, 영역 G는 표적 핵산와 이중체인 경우 뉴클레아제를 구성할 수 있는 뉴클레오시드 단위 10, 11, 12 ,13, 14 또는 15개로 이루어진다.
또 다른 실시양태에서, 올리고뉴클레오티드는, 영역 F 및 F'가 각각 독립적으로 2, 3, 4 또는 5개의 변형 뉴클레오시드 단위, 예를 들면, 2'-O-메톡시에틸-리보스 당(2'-MOE)을 함유하는 뉴클레오시드 단위 또는 2'-플루오로-데옥시리보스 당을 함유하는 뉴클레오시드 단위 및/또는 LNA 단위로 이루어지고, 영역 G가 9, 10, 11, 12, 13, 14 또는 15개의 뉴클레오시드 단위, 예를 들면, DNA 단위 또는 다른 뉴클레아제 구성 뉴클레오시드, 예를 들면, 알파-L-LNA 또는 DNA와 뉴클레아제 구성 뉴클레오시드의 혼합물로 이루어지는 갭머이다.
또 다른 특정 실시양태에서, 올리고뉴클레오티드는 영역 F 및 F'가 각각 2개의 LNA 단위 각각으로 이루어지고, 영역 G가 10, 11, 12, 13, 14 또는 15개의 뉴클레오시드 단위, 바람직하게는 DNA 단위로 이루어지는 갭머이다. 상기 특성을 갖는 특정 갭머 디자인으로는 2-10-2, 2-11-2, 2-12-2, 2-13-2, 2-14-2 및 2-15-2가 포함된다.
또 다른 특정 실시양태에서, 올리고뉴클레오티드는 영역 F 및 F'가 각각 독립적으로 3개의 LNA 단위로 이루어지고, 영역 G가 10, 11, 12, 13, 14 또는 15개의 뉴클레오시드 단위, 바람직하게는 DNA 단위로 이루어지는 갭머이다. 상기 특성을 갖는 특정 갭머 디자인으로는 3-10-3, 3-11-3, 3-12-3, 3-13-3, 3-14-3 및 3-15-3이 포함된다.
또 다른 특정 실시양태에서, 올리고뉴클레오티드는 영역 F 및 F'가 각각 4개의 LNA 단위 각각으로 이루어지고, 영역 G가 10, 11, 12, 13, 14 또는 15개의 뉴클레오시드 단위, 바람직하게는 DNA 단위로 이루어지는 갭머이다. 상기 특성을 갖는 특정 갭머 디자인으로는 4-10-4, 4-11-4, 4-12-4, 4-13-4, 4-14-4 및 4-15-4가 포함된다.
상기 특성을 갖는 특정 갭머 디자인은, 1-10-1, 2-10-1, 1-10-2, 1-10-3, 3-10-1, 1-10-4, 4-10-1, 2-10-2, 2-10-3, 3-10-2, 2-10-4, 4-10-2, 3-10-3, 3-10-4, 4-10-3 및 4-10-4 갭머를 포함하여, 10개의 뉴클레오시드를 갖는 갭 및 날개서열에 독립적으로 1 내지 4개의 변형 뉴클레오시드로 이루어진 군에서 선택된 F-G-F' 디자인을 포함한다.
상기 특성을 갖는 특정 갭머 디자인은, 1-11-1, 2-11-1, 1-11-2, 1-11-3, 3-11-1, 1-11-4, 4-11-1, 2-11-2, 2-11-3, 3-11-2, 2-11-4, 4-11-2, 3-11-3, 3-11-4, 4-11-3 및 4-11-4 갭머를 포함하여, 11개의 뉴클레오시드를 갖는 갭 및 날개서열에 독립적으로 1 내지 4개의 변형 뉴클레오시드로 이루어진 군에서 선택된 F-G-F' 디자인을 포함한다.
상기 특성을 갖는 특정 갭머 디자인은, 1-12-1, 2-12-1, 1-12-2, 1-12-3, 3-12-1, 1-12-4, 4-12-1, 2-12-2, 2-12-3, 3-12-2, 2-12-4, 4-12-2, 3-12-3, 3-12-4, 4-12-3 및 4-12-4 갭머를 포함하여, 12개의 뉴클레오시드를 갖는 갭으로 이루어진 군에서 선택된 F-G-F' 디자인을 포함한다.
상기 특성을 갖는 특정 갭머 디자인은, 1-13-1, 1-13-2, 1-13-3, 3-13-1, 1-13-4, 4-13-1,2-13-1, 2-13-2, 2-13-3, 3-13-2, 2-13-4, , 4-13-2, 3-13-3, 3-13-4, 4-13-3, 및 4-13-4 갭머를 포함하여, 13개의 뉴클레오시드를 갖는 갭 및 날개서열에 독립적으로 1 내지 4개의 변형 뉴클레오시드로 이루어진 군에서 선택된 F-G-F' 디자인을 포함한다.
상기 특성을 갖는 특정 갭머 디자인은, 1-14-1, 1-14-2, 2-14-1, 1-14-3, 3-14-1, 1-14-4, 4-14-1, 2-14-2, 2-14-3, 3-14-2 2-14-4, 4-14-2, 3-14-3, 3-14-4 및 4-14-3 갭머를 포함하여, 14개의 뉴클레오시드를 갖는 갭 및 날개서열에 독립적으로 1 내지 4개의 변형 뉴클레오시드로 이루어진 군에서 선택된 F-G-F' 디자인을 포함한다.
상기 특성을 갖는 특정 갭머 디자인은, 1-15-1, 1-15-2, 2-15-1, 1-15-3, 3-15-1, 1-15-4, 4-15-1, 2-15-2, 2-15-3, 3-15-2 2-15-4, 4-15-2, 3-15-3, 3-15-4 및 4-15-3 갭머를 포함하여, 15개의 뉴클레오시드를 갖는 갭 및 날개서열에 독립적으로 1 내지 4개의 변형 뉴클레오시드로 이루어진 군에서 선택된 F-G-F' 디자인을 포함한다.
상기 특성을 갖는 특정 갭머 디자인은, 1-16-1, 1-16-2, 2-16-1, 1-15-3, 3-16-1, 1-16-4, 4-16-1, 2-16-2, 2-16-3, 3-16-2 2-16-4, 4-16-2, 3-16-3, 3-16-4 및 4-16-3 갭머를 포함하여, 16개의 뉴클레오시드를 갖는 갭 및 날개서열에 독립적으로 1 내지 4개의 변형 뉴클레오시드로 이루어진 군에서 선택된 F-G-F' 디자인을 포함한다.
일부 실시양태에서, F-G-F' 디자인은 2-10-4, 3-10-3 및 4-10-2로부터 선택된다.
일부 실시양태에서, F-G-F' 디자인은 2-11-4, 3-11-2, 3-11-3 및 4-11-2로부터 선택된다.
일부 실시양태에서, F-G-F' 디자인은 2-12-2, 2-12-3, 2-12-4, 3-12-2, 3-12-3, 및 4-12-2로부터 선택된다.
일부 실시양태에서, F-G-F' 디자인은 2-13-2, 2-13-3, 2-13-4, 3-13-3 및 4-13-2로부터 선택된다.
일부 실시양태에서, F-G-F' 디자인은 2-14-2, 2-14-4, 3-14-3 및 4-14-2로부터 선택된다.
일부 실시양태에서, F-G-F' 디자인은 2-15-2 및 2-16-2로부터 선택된다.
일부 실시양태에서, F-G-F' 디자인은 표 3에 나타낸 디자인들로부터 선택된다.
모든 경우에서, F-G-F' 디자인은, 1, 2 또는 3개의 뉴클레오시드 단위, 예를 들면, DNA 단위를 가질 수 있는 영역 D 및/또는 D'를 추가로 포함할 수 있다. 바람직하게, 영역 F 및 F' 내의 뉴클레오시드는 변형 뉴클레오시드인 반면, 영역 G 내의 뉴클레오시드는 바람직하게는 비변형 뉴클레오시드이다.
각각의 디자인에서, 바람직한 변형 뉴클레오시드는 LNA이다.
또 다른 실시양태에서, 갭머내 갭 중의 뉴클레오시드간 결합은 포스포로티오에이트 및/또는 보라노포스페이트 결합이다. 또 다른 실시양태에서 갭머 내 측면서열(F 및 F' 영역) 중 뉴클레오시드간 결합은 모두 포스포로티오에이트 및/또는 보라노포스페이트 결합이다. 또 다른 바람직한 실시양태에서, 갭머내 D 및 D' 영역 중 뉴클레오시드간 결합은 모두 포스포다이에스터 결합이다.
본원에서 개시된 바와 같은 특정 갭머의 경우, 시토신(C) 잔기가 5-메틸-시토신으로 주석이 달린 경우, 다양한 실시양태에서, 올리고뉴클레오티드에 존재하는 C 중 하나 이상이 비변형된 C 잔기일 수 있다.
또 다른 갭머 디자인이 WO2004/046160 호, WO2007/146511 호에 개시되어 있으며 참고로 도입된다.
본 발명의 특정 실시양태에 있어서, 올리고뉴클레오티드는 표 3의 올리고뉴클레오티드 화합물들의 군에서 선택된다.
본 발명의 특정 실시양태에 있어서, 올리고뉴클레오티드는 CMP 번호 4_1 내지 150_2의 올리고뉴클레오티드 화합물들의 군에서 선택된다.
본 발명의 특정 실시양태에 있어서, 올리고뉴클레오티드는 CMP 번호 4_1 내지 678_1의 올리고뉴클레오티드 화합물들의 군에서 선택된다.
본 발명의 특정 실시양태에 있어서, 올리고뉴클레오티드는 CMP 번호 4_1 내지 818_1의 올리고뉴클레오티드 화합물들의 군에서 선택된다(실시예 부분의 표 3에 열거된 올리고뉴클레오티드 서열 참조).
본 발명의 특정 실시양태에 있어서, 올리고뉴클레오티드는 CMP 번호 155_1 또는 165_1의 올리고뉴클레오티드 화합물이다.
본 발명의 특정 실시양태에 있어서, 올리고뉴클레오티드는 CMP 번호 169_52, 169_50 또는 169_56의 올리고뉴클레오티드 화합물들의 군에서 선택된다.
본 발명의 특정 실시양태에 있어서, 올리고뉴클레오티드는 CMP 번호 172_1, 272_1, 572_7, 572_6 or 572_5의 올리고뉴클레오티드 화합물들의 군에서 선택된다.
본 발명의 특정 실시양태에 있어서, 올리고뉴클레오티드는 CMP 번호 175_1의 올리고뉴클레오티드 화합물이다.
본 발명의 특정 실시양태에 있어서, 올리고뉴클레오티드는 CMP 번호 178_1의 올리고뉴클레오티드 화합물이다.
본 발명의 특정 실시양태에 있어서, 올리고뉴클레오티드는 CMP 번호 573_8, 186_1 또는 187_1의 올리고뉴클레오티드 화합물들의 군에서 선택된다.
본 발명의 특정 실시양태에 있어서, 올리고뉴클레오티드는 CMP 번호 186_1의 올리고뉴클레오티드 화합물이다.
본 발명의 특정 실시양태에 있어서, 올리고뉴클레오티드는 CMP 번호 200_1, 204_1, 206_1, 35_2 또는 209_1의 올리고뉴클레오티드 화합물들의 군에서 선택된다.
본 발명의 특정 실시양태에 있어서, 올리고뉴클레오티드는 CMP 번호 585_1, 585_8, 586_9, 586_5, 586_8, 586_4 또는 586_6의 올리고뉴클레오티드 화합물들의 군에서 선택된다.
본 발명의 특정 실시양태에 있어서, 올리고뉴클레오티드는 CMP 번호 233_1의 올리고뉴클레오티드 화합물이다.
본 발명의 특정 실시양태에 있어서, 올리고뉴클레오티드는 CMP 번호 237_8 또는 590_13의 올리고뉴클레오티드 화합물이다.
본 발명의 특정 실시양태에 있어서, 올리고뉴클레오티드는 CMP 번호 220_1의 올리고뉴클레오티드 화합물이다.
본 발명의 특정 실시양태에 있어서, 올리고뉴클레오티드는 CMP 번호 591_1, 592_2, 592_4 또는 241_9의 올리고뉴클레오티드 화합물들의 군에서 선택된다.
본 발명의 특정 실시양태에 있어서, 올리고뉴클레오티드는 CMP 번호 597_4, 598_4, 39_1 또는 602_1의 올리고뉴클레오티드 화합물들의 군에서 선택된다.
본 발명의 특정 실시양태에 있어서, 올리고뉴클레오티드는 CMP 번호 39_1의 올리고뉴클레오티드 화합물이다.
본 발명의 특정 실시양태에 있어서, 올리고뉴클레오티드는 CMP 번호 611_7의 올리고뉴클레오티드 화합물이다.
본 발명의 특정 실시양태에 있어서, 올리고뉴클레오티드는 CMP 번호 271_1 또는 278_1의 올리고뉴클레오티드 화합물이다.
본 발명의 특정 실시양태에 있어서, 올리고뉴클레오티드는 CMP 번호 616_4, 621_2, 621_1, 622_3, 622_5, 622_4, 624_3, 624_5, 287_1, 625_6, 626_7, 626_8, 626_9, 48_1, 631_6, 631_1, 303_1, 304_6 또는 304_10의 올리고뉴클레오티드 화합물들의 군에서 선택된다.
본 발명의 특정 실시양태에 있어서, 올리고뉴클레오티드는 CMP 번호 636_8의 올리고뉴클레오티드 화합물이다.
본 발명의 특정 실시양태에 있어서, 올리고뉴클레오티드는 CMP 번호 638_8, 639_5, 331_1 또는 640_4의 올리고뉴클레오티드 화합물들의 군에서 선택된다.
본 발명의 특정 실시양태에 있어서, 올리고뉴클레오티드는 CMP 번호 359_1, 361_1, 361_5, 362_1 또는 641_5의 올리고뉴클레오티드 화합물들의 군에서 선택된다.
본 발명의 특정 실시양태에 있어서, 올리고뉴클레오티드는 CMP 번호 378_1, 379_1, 399_1의 올리고뉴클레오티드 화합물들의 군에서 선택된다.
본 발명의 특정 실시양태에 있어서, 올리고뉴클레오티드는 CMP 번호 403_1, 405_1, 642_12, 642_13, 644_3 또는 646_16의 올리고뉴클레오티드 화합물들의 군에서 선택된다.
본 발명의 특정 실시양태에 있어서, 올리고뉴클레오티드는 CMP 번호 85_1 또는 425_5의 올리고뉴클레오티드 화합물이다.
본 발명의 특정 실시양태에 있어서, 올리고뉴클레오티드는 CMP 번호 116_1의 올리고뉴클레오티드 화합물이다.
본 발명의 특정 실시양태에 있어서, 올리고뉴클레오티드는 CMP 번호 123_1 또는 124_1의 올리고뉴클레오티드 화합물이다.
본 발명의 특정 실시양태에 있어서, 올리고뉴클레오티드는 CMP 번호 126_2의 올리고뉴클레오티드 화합물이다.
제조 방법
또 다른 양태에서, 본 발명은, 뉴클레오티드 단위들을 반응시켜 올리고뉴클레오티드에 포함되는 공유 결합된 연속 뉴클레오티드 단위를 생성시키는 것을 포함하는, 본 발명의 올리고뉴클레오티드를 제조하는 방법을 제공한다. 바람직하게, 상기 방법은 포스포르아미다이트 화합물을 사용한다(예를 들면, 문헌 [Caruthers et al, 1987, Methods in Enzymology vol. 154, pages 287-313] 참조). 또 다른 실시양태에서, 상기 방법은 연속 뉴클레오티드 서열을 접합 잔기(리간드)와 반응시키는 것을 추가로 포함한다. 또 다른 양태에서, 본 발명의 올리고뉴클레오티드 또는 접합된 올리고뉴클레오티드를 약학적으로 허용되는 희석제, 용매, 담체, 염 및/또는 보조제와 혼합하는 것을 포함하는, 본 발명의 조성물을 제조하는 방법이 제공된다.
약학 조성물
또 다른 양태에서, 본 발명은 임의의 전술한 올리고뉴클레오티드 및/또는 올리고뉴클레오티드 접합체 및 약학적으로 허용되는 희석제, 담체, 염 및/또는 보조제를 포함하는 약학 조성물을 제공한다. 약학적으로 허용되는 희석제는 포스페이트-완충 식염수(PBS)를 포함하고, 약학적으로 허용되는 염은 나트륨 및 칼륨 염을 포함하나 이로 한정되지는 않는다.
WO 2007/031091 호는 약학적으로 허용되는 희석제, 담체 및 보조제의 적절하고 바람직한 예들을 제공한다(본원에 참고로 도입됨). 적절한 투여향, 제형, 투여 경로, 조성물, 투여형, 다른 치료제와의 병용, 전구-약물 제형도 또한 WO 2007/031091 호에 제공되어 있다.
본 발명의 올리고뉴클레오티드 또는 올리고뉴클레오티드 접합체는 약학 조성물 또는 제형의 제조를 위해 약학적으로 허용되는 활성 물질 또는 불활성 물질과 혼합될 수 있다. 약학 조성물의 제형화를 위한 조성 및 방법은 투여 경로, 질환의 정도 또는 투여될 용량을 포함하지만 이로 한정되지는 않는 많은 기준에 따라 달라진다.
일부 실시양태에서, 본 발명의 올리고뉴클레오티드 또는 올리고뉴클레오티드 접합체는 전구약물이다. 특히, 올리고뉴클레오티드 접합체와 관련하여, 접합체 잔기는, 일단 전구약물이 작용 부위, 예를 들면, 표적 세포에 전달되면, 올리고뉴클레오티드로부터 분리된다.
용도
본 발명의 올리고뉴클레오티드는, 예를 들면, 치료 및 예방을 위한 연구용 시약으로 사용될 수 있다.
연구에서, 상기 올리고뉴클레오티드는 세포(예를 들면, 시험관내 세포 배양물) 및 실험 동물에서 UBE3A 단백질의 합성을 특이적으로 조절하여 표적의 기능 분석 또는 치료적 개입을 위한 표적으로서 그의 유용성의 평가를 촉진하기 위해 사용될 수 있다. 표적 조절은 단백질을 생성하는 유전자 또는 mRNA의 조절인자를 분해시키거나 억제함으로써 달성된다.
치료의 경우, 질환 또는 장애를 갖는 것으로 의심되는 동물 또는 인간은 UBE3A의 발현을 조절함으로써 치료될 수 있다.
본 발명은, 치료 또는 예방 효과량의 본 발명의 올리고뉴클레오티드, 올리고뉴클레오티드 접합체 또는 약학 조성물을 질환을 앓고 있거나 질환에 걸리기 쉬운 대상에게 투여하는 것을 포함하는, 질환을 치료 또는 예방하는 방법을 제공한다.
본 발명은 또한 약제로서 사용하기 위한, 본원에 정의된 바와 같은 올리고뉴클레오티드, 조성물 또는 접합체에 관한 것이다.
본 발명에 따른 올리고뉴클레오티드, 올리고뉴클레오티드 접합체 또는 약학 조성물은 전형적으로 효과량으로 투여된다.
본 발명은 또한 본원에서 언급된 바와 같은 장애의 치료를 위한 약제의 제조를 위한, 기술된 바와 같은 본 발명의 올리고뉴클레오티드 또는 올리고뉴클레오티드 접합체의 용도, 또는 본원에서 언급된 바와 같은 장애의 치료 방법을 제공한다.
본원에서 언급된 바와 같은 질환 또는 장애는 UBE3A의 발현과 연관된다. 일부 실시양태에서, 상기 질환 또는 장애는 성숙 UBE3A 유전자에서의 돌연변이와 연관될 수 있다. 일부 실시양태에서, 표적 핵산은 부계 UBE3A의 조절자이다.
본 발명의 방법은 바람직하게는 UBE3A의 비정상적 수준 및/또는 활성에 의해 야기된 질환에 대한 치료 또는 예방에 사용된다. 상기 질환은 특히 UBE3A 단백질의 감소된 수준 및/또는 활성에 의해 야기될 수 있다.
본 발명은 또한 UBE3A의 비정상적 수준 및/또는 활성, 특히 UBE3A의 낮은 수준 및/또는 활성의 치료를 위한 약제의 제조를 위한, 본원에서 정의된 바와 같은 올리고뉴클레오티드, 올리고뉴클레오티드 접합체 또는 약학 조성물의 용도에 관한 것이다.
한 실시양태에서, 본 발명은 엔젤만 증후군의 치료에 사용하기 위한 올리고뉴클레오티드, 올리고뉴클레오티드 접합체 또는 약학 조성물에 관한 것이다.
투여
본 발명의 올리고뉴클레오티드 또는 약학 조성물은 국소적으로(예를 들면, 피부에, 흡입, 눈 또는 귀에) 또는 장내에(예를 들면, 경구적으로 또는 위장관을 통해) 또는 비경구적으로(예를 들면, 정맥내, 피하, 근육내, 대뇌내, 뇌실내 또는 척추강내) 투여될 수 있다.
바람직한 실시양태에서, 본 발명의 올리고뉴클레오티드 또는 약학 조성물은 정맥내, 동맥내, 피하, 복강내 또는 근육내 주사 또는 주입, 척추강내 또는 두개내, 예를 들면, 대뇌내 또는 뇌실내 투여를 포함한 비경구적 경로에 의해 투여된다. 한 실시양태에서, 활성 올리고뉴클레오티드 또는 올리고뉴클레오티드 접합체는 대뇌내 또는 뇌실내 투여된다. 또 다른 실시양태에서, 활성 올리고뉴클레오티드 또는 올리고뉴클레오티드 접합체는 척추강내로 투여된다.
본 발명은 또한 약제가 척추강내 투여를 위한 투여형인 약제의 제조를 위한, 기술된 바와 같은 본 발명의 올리고뉴클레오티드 또는 올리고뉴클레오티드 접합체의 용도를 제공한다.
본 발명은 또한 약제가 대뇌내 또는 뇌실내 투여를 위한 투여형인 약제의 제조를 위한, 기술된 바와 같은 본 발명의 올리고뉴클레오티드 또는 올리고뉴클레오티드 접합체의 용도를 제공한다.
본 발명은 또한 약제가 뇌실내 투여를 위한 투여형인 약제의 제조를 위한, 기술된 바와 같은 본 발명의 올리고뉴클레오티드 또는 올리고뉴클레오티드 접합체의 용도를 제공한다.
병용 치료
일부 실시양태에서, 본 발명의 올리고뉴클레오티드, 올리고뉴클레오티드 접합체 또는 약학 조성물은 또 다른 치료제와의 병용 치료에 사용하기 위한 것이다. 치료제는, 예를 들면, 항경련 약제일 수 있다.
실시양태들
본 발명의 하기의 실시양태들은 본원에 기술된 임의의 다른 실시양태들과 함께 사용될 수 있다.
1. 특히 뉴런 세포에서 인간 부계 UBE3A 발현을 유도할 수 있는, 10 내지 30개 뉴클레오티드 길이의 연속 뉴클레오티드 서열을 포함하거나 그로 이루어지는 안티센스 올리고뉴클레오티드.
2. 연속 뉴클레오티드 서열이 염색체 15 상의 위치 25278410 내지 25419462에 상응하는, SNORD109B의 하류의 인간 SNHG14 긴 비-암호화 RNA 부분에 대해 95% 이상의 상보성을 갖는, 실시양태 1의 올리고뉴클레오티드.
3. -10 kcal 미만의 ΔG°하에 서열번호 1의 표적 핵산에 하이브리드화될 수 있는, 실시양태 1 또는 2의 올리고뉴클레오티드.
4. 연속 뉴클레오티드 서열이 서열번호 1 및/또는 2의 표적 핵산 영역에 95% 이상, 예를 들면, 98% 이상, 예를 들면, 100%의 상보성을 갖는, 실시양태 1 내지 3의 올리고뉴클레오티드.
5. 연속 뉴클레오티드 서열이 서열번호 1의 위치 1 내지 55318의 표적 핵산 영역에 100% 상보적인, 실시양태 1 내지 3의 올리고뉴클레오티드.
6. 연속 뉴클레오티드 서열이 표적 핵산의 아서열에 상보적이고, 상기 아서열이 표 1 또는 2에 나타낸 영역들로 이루어진 군에서 선택되는, 실시양태 1 내지 4의 올리고뉴클레오티드.
7. 연속 뉴클레오티드 서열이 UBE3A 전구체-mRNA에 대해 안티센스인 인간 SNHG14 긴 비-암호화 RNA 부분에 대해 98% 이상의 상보성을 갖는, 실시양태 1 내지 4의 올리고뉴클레오티드.
8. -10 kcal 미만의 ΔG°하에 서열번호 1의 위치 55319 내지 141053에 상응하는 표적 핵산에 하이브리드화될 수 있는, 실시양태 1 내지 4 또는 7의 올리고뉴클레오티드.
9. 연속 뉴클레오티드 서열이 서열번호 1의 위치 55319 내지 141053의 표적 핵산에 100% 상보적인, 실시양태 1 내지 4 또는 7 내지 8의 올리고뉴클레오티드.
10. 표적 핵산이 RNA인, 실시양태 1 내지 8의 올리고뉴클레오티드.
11. RNA가 긴 비-암호화 RNA인, 실시양태 10의 올리고뉴클레오티드.
12. 연속 뉴클레오티드 서열이 10개 이상의 연속 뉴클레오티드, 특히 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28 또는 29개의 연속 뉴클레오티드를 포함하거나 그로 이루어진, 실시양태 1 내지 11의 올리고뉴클레오티드.
13. 연속 뉴클레오티드 서열이 12 내지 22개의 뉴클레오티드를 포함하거나 그로 이루어진, 실시양태 1 내지 12의 올리고뉴클레오티드.
14. 연속 뉴클레오티드 서열이 15 내지 20개의 뉴클레오티드를 포함하거나 그로 이루어진, 실시양태 13의 올리고뉴클레오티드.
15. 길이에 있어서 10 내지 35개의 뉴클레오티드를 포함하거나 그로 이루어진, 실시양태 1 내지 14의 올리고뉴클레오티드.
16. 길이에 있어서 15 내지 24개의 뉴클레오티드를 포함하거나 그로 이루어진, 실시양태 15의 올리고뉴클레오티드.
17. 길이에 있어서 17 내지 22개의 뉴클레오티드를 포함하거나 그로 이루어진, 실시양태 15 또는 17의 올리고뉴클레오티드.
18. 올리고뉴클레오티드 또는 연속 뉴클레오티드 서열이 단일 가닥인, 실시양태 1 내지 17의 올리고뉴클레오티드.
19. 연속 뉴클레오티드 서열이 표 1 또는 2에 나타낸 영역들로 이루어진 군에서 선택된 표적 핵산의 아서열에 상보적인, 실시양태 1 내지 18의 올리고뉴클레오티드.
20. 연속 뉴클레오티드 서열이 서열번호 1의 위치 1589 내지 10889, 46089 내지 53989 및 60789 내지 62489로 이루어진 군에서 선택된 표적 핵산의 아서열에 상보적인, 실시양태 1 내지 18의 올리고뉴클레오티드.
21. 연속 뉴클레오티드 서열이 서열번호 1의 위치 5218 내지 5240에 상응하는 표적 핵산의 아서열에 상보적인, 실시양태 1 내지 18의 올리고뉴클레오티드.
22. 연속 뉴클레오티드 서열이 서열번호 1의 위치 5782 내지 5803에 상응하는 표적 핵산의 아서열에 상보적인, 실시양태 1 내지 18의 올리고뉴클레오티드.
23. 연속 뉴클레오티드 서열이 서열번호 1의 위치 8113 내지 8139에 상응하는 표적 핵산의 아서열에 상보적인, 실시양태 1 내지 18의 올리고뉴클레오티드.
24. 연속 뉴클레오티드 서열이 서열번호 1의 위치 9200 내지 9250에 상응하는 표적 핵산의 아서열에 상보적인, 실시양태 1 내지 18의 올리고뉴클레오티드.
25. 연속 뉴클레오티드 서열이 서열번호 1의 위치 11505 내지 11555에 상응하는 표적 핵산의 아서열에 상보적인, 실시양태 1 내지 18의 올리고뉴클레오티드.
26. 연속 뉴클레오티드 서열이 서열번호 1의 위치 13223 내지 13242에 상응하는 표적 핵산의 아서열에 상보적인, 실시양태 1 내지 18의 올리고뉴클레오티드.
27. 연속 뉴클레오티드 서열이 서열번호 1의 위치 15100 내지 15150에 상응하는 표적 핵산의 아서열에 상보적인, 실시양태 1 내지 18의 올리고뉴클레오티드.
28. 연속 뉴클레오티드 서열이 서열번호 1의 위치 15113 내지 15180에 상응하는 표적 핵산의 아서열에 상보적인, 실시양태 1 내지 18의 올리고뉴클레오티드.
29. 연속 뉴클레오티드 서열이 서열번호 1의 위치 29635 내지 29705에 상응하는 표적 핵산의 아서열에 상보적인, 실시양태 1 내지 18의 올리고뉴클레오티드.
30. 연속 뉴클레오티드 서열이 서열번호 1의 위치 30590 내지 30740에 상응하는 표적 핵산의 아서열에 상보적인, 실시양태 1 내지 18의 올리고뉴클레오티드.
31. 연속 뉴클레오티드 서열이 서열번호 1의 위치 39800 내지 39855에 상응하는 표적 핵산의 아서열에 상보적인, 실시양태 1 내지 18의 올리고뉴클레오티드.
32. 연속 뉴클레오티드 서열이 서열번호 1의 위치 44435 내지 44460에 상응하는 표적 핵산의 아서열에 상보적인, 실시양태 1 내지 18의 올리고뉴클레오티드.
33. 연속 뉴클레오티드 서열이 서열번호 1의 위치 45245 내지 45270에 상응하는 표적 핵산의 아서열에 상보적인, 실시양태 1 내지 18의 올리고뉴클레오티드.
34. 연속 뉴클레오티드 서열이 서열번호 1의 위치 46380 내지 46430에 상응하는 표적 핵산의 아서열에 상보적인, 실시양태 1 내지 18의 올리고뉴클레오티드.
35. 연속 뉴클레오티드 서열이 서열번호 1의 위치 68915 내지 68940에 상응하는 표적 핵산의 아서열에 상보적인, 실시양태 1 내지 18의 올리고뉴클레오티드.
36. siRNA도 아니고 자기-상보적이지도 않은, 실시양태 1 내지 35의 올리고뉴클레오티드.
37. 연속 뉴클레오티드 서열이 서열번호 1. 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 1819, 20, 21, 22, 23, 23, 24, 25, 26, 26, 27, 28, 29, 30, 31, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 44, 45, 45, 46, 47, 48, 49, 50, 51, 52, 53, 53, 54, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 79, 80, 81, 8283, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 95, 96, 96, 96, 97, 98, 99, 100, 101, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135, 136, 137, 138, 139, 140, 141, 142, 143, 144, 145, 146, 147, 148, 149, 150, 151, 152, 153, 154, 155, 156, 157, 158, 159, 160, 161, 162, 163, 164, 165, 166, 167, 168, 169, 170, 171, 172, 173, 174, 175, 176, 177, 178, 179, 180, 181, 182, 183, 184, 185, 186, 187, 188, 189, 190, 191, 192, 193, 194, 195, 196, 197, 198, 199, 200, 201, 202, 203, 204, 205, 206, 207, 208, 209, 210, 211, 212, 213, 214, 215, 216, 217, 218, 219, 220, 221, 222, 223, 224, 225, 226, 227, 228, 229, 230, 231, 232, 233, 234, 235, 236, 237, 238, 239, 240, 241, 242, 243, 244, 245, 246, 247, 248, 249, 250, 251, 252, 253, 254, 255, 256, 257, 258, 259, 260, 261, 262, 263, 264, 265, 266, 267, 268, 269, 270, 271, 272, 273, 274, 275, 276, 277, 278, 279, 280, 281, 282, 283, 284, 285, 286, 287, 288, 289, 290, 291, 292, 293, 294, 295, 296, 297, 298, 299, 300, 301, 302, 303, 304, 304, 305, 306, 307, 308, 309, 310, 311, 312, 313, 314, 315, 316, 317, 318, 319, 320, 321, 322, 323, 324, 325, 326, 327, 328, 329, 330, 331, 332, 333, 334, 335, 336, 337, 338, 339, 340, 341, 342, 343, 344, 345, 346, 347, 348, 349, 350, 351, 352, 353, 354, 355, 356, 357, 358, 359, 360, 361, 362, 363, 364, 365, 366, 367, 368, 369, 370, 371, 372, 373, 374, 375, 376, 377, 378, 379, 380, 381, 382, 383, 384, 385, 386, 387, 388, 389, 390, 391, 392, 393, 394, 395, 396, 397, 398, 399, 400, 401, 402, 403, 404, 405, 406, 407, 408, 409, 410, 411, 412, 413, 414, 415, 416, 417, 418, 419, 420, 421, 422, 423, 424, 425, 426, 427, 428, 429, 430, 431, 432, 433, 434, 435, 436, 437, 438, 439, 440, 441, 442, 443, 444, 445, 446, 447, 448, 449, 450, 451, 452, 453, 454, 455, 456, 457, 458, 459, 460, 461, 462, 463, 464, 465, 466, 467, 468, 469, 470, 471, 472, 473, 474, 475, 476, 477, 478, 479, 480, 481, 482, 483, 484, 485, 486, 487, 488, 489, 490, 491, 492, 493, 494, 495, 496, 497, 498, 499, 500, 501, 502, 503, 504, 505, 506, 507, 508, 509, 510, 511, 512, 513, 514, 515, 516, 517, 518, 519, 520, 521, 522, 523, 524, 525, 526, 527, 528, 529, 530, 531, 532, 533, 534, 535, 536, 537, 538, 539, 540, 541, 542, 543, 544, 545, 546, 547, 548, 549, 550, 551, 552, 553, 554, 555, 556, 557, 558, 559, 560, 561, 562, 563, 564, 565, 566, 567, 568, 569, 570, 571, 572, 573, 574, 575, 576, 577, 578, 579, 580, 581, 582, 583, 584, 585, 586, 587, 588, 589, 590, 591, 592, 593, 594, 595, 596, 596, 597, 598, 599, 600, 601, 602, 603, 604, 605, 606, 607, 608, 609, 610, 611, 612, 613, 614, 615, 616, 617, 618, 619, 620, 621, 622, 623, 624, 625, 626, 627, 628, 629, 630, 631, 632, 633, 634, 635, 636, 637, 638, 639, 640, 641, 642, 643, 644, 645, 646, 647, 648, 649, 650, 651, 652, 653, 654, 655, 656, 657, 658, 659, 660, 661, 662, 663, 664, 665, 666, 667, 668, 669, 670, 671, 672, 673, 674, 675, 676, 677, 678, 679, 680, 681, 682, 683, 684, 685, 686, 687, 688, 689, 690, 691, 692, 693, 694, 695, 696, 697, 698, 699, 700, 702, 703, 704, 705, 706, 707, 708, 709, 710, 711, 712, 713, 714, 715, 716, 717, 718, 719, 719, 720, 721, 722, 723, 724, 725, 726, 727, 728, 729, 730, 731, 732, 733, 734, 735, 736, 737, 738, 739, 740, 741, 742, 743, 744, 745, 746, 747, 748, 749, 750, 751, 752, 754, 755, 756, 757, 758, 759, 760, 761, 762, 763, 764, 765, 766, 767, 768, 769, 770, 772, 773, 774, 775, 776, 777, 778, 779, 780, 781, 782, 783, 784, 785, 786, 787, 788, 789, 790, 791, 792, 793, 794, 795, 796, 797, 798, 799, 800, 801, 802, 803, 804, 805, 806, 807, 808, 809, 810, 811, 812, 813, 814, 815, 816, 817 및 818로 이루어진 군에서 선택된 서열을 포함하거나 그로 이루어진, 실시양태 1 내지 36의 올리고뉴클레오티드.
38. 연속 뉴클레오티드 서열이 서열번호 166, 167 또는 169(실시예 부분의 표 3에 열거된 모티스 서열 참조)로 이루어진 군에서 선택된 서열을 포함하거나 그로 이루어지는, 실시양태 1 내지 36의 올리고뉴클레오티드.
39. 연속 뉴클레오티드 서열이 서열번호 570, 571 ,572, 679, 680, 681, 682 및 683(실시예 부분의 표 3에 열거된 모티스 서열 참조)로 이루어진 군에서 선택된 서열을 포함하거나 그로 이루어지는, 실시양태 1 내지 36의 올리고뉴클레오티드.
40. 연속 뉴클레오티드 서열이 서열번호 570, 571 ,572, 679, 680, 681, 682 및 683(실시예 부분의 표 3에 열거된 모티스 서열 참조)로 이루어진 군에서 선택된 서열을 포함하거나 그로 이루어지는, 실시양태 1 내지 36의 올리고뉴클레오티드.
41. 연속 뉴클레오티드 서열이 서열번호 35, 199 내지 210 또는 서열번호 582 내지 584(실시예 부분의 표 3에 열거된 모티스 서열 참조)로 이루어진 군에서 선택된 서열을 포함하거나 그로 이루어지는, 실시양태 1 내지 36의 올리고뉴클레오티드.
42. 연속 뉴클레오티드 서열이 서열번호 236, 237, 238, 239, 240 및 590(실시예 부분의 표 3에 열거된 모티스 서열 참조)으로 이루어진 군에서 선택된 서열을 포함하거나 그로 이루어지는, 실시양태 1 내지 36의 올리고뉴클레오티드.
43. 연속 뉴클레오티드 서열이 서열번호 221 내지 225 또는 서열번호 585 내지 589(실시예 부분의 표 3에 열거된 모티스 서열 참조)로 이루어진 군에서 선택된 서열을 포함하거나 그로 이루어지는, 실시양태 1 내지 36의 올리고뉴클레오티드.
44. 연속 뉴클레오티드 서열이 서열번호 241 또는 591(실시예 부분의 표 3에 열거된 모티스 서열 참조)로 이루어진 군에서 선택된 서열을 포함하거나 그로 이루어지는, 실시양태 1 내지 36의 올리고뉴클레오티드.
45. 연속 뉴클레오티드 서열이 서열번호 46 내지 48, 285 내지 305 또는 서열번호 613 내지 632 또는 서열번호 721 내지 807(실시예 부분의 표 3에 열거된 모티스 서열 참조)로 이루어진 군에서 선택된 서열을 포함하거나 그로 이루어지는, 실시양태 1 내지 36의 올리고뉴클레오티드.
46. 연속 뉴클레오티드 서열이 서열번호 331, 332, 638, 639, 640, 808, 809, 810, 811, 812, 813, 814 및 815(실시예 부분의 표 3에 열거된 모티스 서열 참조)로 이루어진 군에서 선택된 서열을 포함하거나 그로 이루어지는, 실시양태 1 내지 36의 올리고뉴클레오티드.
47. 연속 뉴클레오티드 서열이 서열번호 409 내지 411 또는 서열번호 642 내지 646 또는 서열번호 816 내지 818(실시예 부분의 표 3에 열거된 모티스 서열 참조)로 이루어진 군에서 선택된 서열을 포함하거나 그로 이루어지는, 실시양태 1 내지 36의 올리고뉴클레오티드.
48. 연속 뉴클레오티드 서열이 상보적인 표적 핵산과 비교하여 0 내지 3개의 미스매치를 갖는, 실시양태 1 내지 47의 올리고뉴클레오티드.
49. 연속 뉴클레오티드 서열이 표적 핵산과 비교하여 1개의 미스매치를 갖는, 실시양태 48의 올리고뉴클레오티드.
50. 연속 뉴클레오티드 서열이 표적 핵산과 비교하여 2개의 미스매치를 갖는, 실시양태 48의 올리고뉴클레오티드.
51. 연속 뉴클레오티드 서열이 표적 핵산 서열에 완전히 상보적인, 실시양태 48의 올리고뉴클레오티드.
52. 1개 이상의 변형 뉴클레오시드를 포함하는, 실시양태 1 내지 51의 올리고뉴클레오티드.
53. 1개 이상의 변형 뉴클레오시드가 고-친화성 변형된 뉴클레오시드인, 실시양태 52의 올리고뉴클레오티드.
54. 1개 이상의 변형 뉴클레오시드가 2' 당 변형된 뉴클레오시드인, 실시양태 52 또는 53의 올리고뉴클레오티드.
55. 1개 이상의 2' 당 변형된 뉴클레오시드가 2'-O-알킬-RNA, 2'-O-메틸-RNA, 2'-알콕시-RNA, 2'-O-메톡시에틸-RNA, 2'-아미노-DNA, 2'-플루오로-DNA, 2'-플루오로-ANA 및 LNA 뉴클레오시드로 이루어진 군에서 독립적으로 선택되는, 실시양태 54의 올리고뉴클레오티드.
56. 1개 이상의 변형 뉴클레오시드가 LNA 뉴클레오시드인, 실시양태 54의 올리고뉴클레오티드.
57. 변형 LNA 뉴클레오시드가 옥시-LNA인, 실시양태 56의 올리고뉴클레오티드.
58. 변형 뉴클레오시드가 베타-D-옥시-LNA인, 실시양태 57의 올리고뉴클레오티드.
59. 변형 뉴클레오시드가 알파-L-옥시-LNA인, 실시양태 57의 올리고뉴클레오티드.
60. 변형 뉴클레오시드가 티오-LNA인, 실시양태 56의 올리고뉴클레오티드.
61. 변형 뉴클레오시드가 아미노-LNA인, 실시양태 56의 올리고뉴클레오티드.
62. 변형 뉴클레오시드가 cET인, 실시양태 56의 올리고뉴클레오티드.
63. 변형 뉴클레오시드가 ENA인, 실시양태 56의 올리고뉴클레오티드.
64. 변형 LNA 뉴클레오시드가 베타-D-옥시-LNA, 알파-L-옥시-LNA, 베타-D-아미노-LNA, 알파-L-아미노-LNA, 베타-D-티오-LNA, 알파-L-티오-LNA, (S)cET, (R)cET 베타-D-ENA 및 알파-L-ENA로부터 선택되는, 실시양태 56의 올리고뉴클레오티드.
65. 1개 이상의 변형된 뉴클레오시드간 결합을 포함하는, 실시양태 1 내지 64 중 어느 하나의 올리고뉴클레오티드.
66. 변형된 뉴클레오시드간 결합이 뉴클레아제 내성인, 실시양태 65의 올리고뉴클레오티드.
67. 연속 뉴클레오티드 서열내 뉴클레오시드간 결합의 50% 이상이 포스포로티오에이트 뉴클레오시드간 결합 또는 보라노포스페이트 뉴클레오시드간 결합인, 실시양태 65 또는 66의 올리고뉴클레오티드.
68. 연속 뉴클레오티드 서열내 모든 뉴클레오시드간 결합이 포스포로티오에이트 뉴클레오시드간 결합인, 실시양태 65 또는 66의 올리고뉴클레오티드.
69. RNase H를 구성할 수 있는, 실시양태 1 내지 68의 올리고뉴클레오티드.
70. 갭머인, 실시양태 69의 올리고뉴클레오티드.
71. 식 5'-F-G-F'-3'의 갭머이고, 이때 영역 F 및 F'는 독립적으로 1 내지 7개의 변형 뉴클레오시드를 포함하거나 그로 이루어지고 G는 RNaseH를 구성할 수 있는 6 내지 16개 뉴클레오시드의 영역인, 실시양태 69 또는 70의 올리고뉴클레오티드.
72. 2' 당 변형된 뉴클레오시드가 2'-O-알킬-RNA, 2'-O-메틸-RNA, 2'-알콕시-RNA, 2'-O-메톡시에틸-RNA, 2'-아미노-DNA, 2'-플루오로-DNA, 아라비노 핵산(ANA), 2'-플루오로-ANA 및 LNA 뉴클레오시드로 이루어진 군에서 독립적으로 선택되는, 실시양태 71의 올리고뉴클레오티드.
73. 영역 F 및 F'의 변형 뉴클레오시드들 중 하나 이상이 LNA 뉴클레오시드인, 실시양태 71 또는 72의 올리고뉴클레오티드.
74. 영역 F 및 F'의 모든 변형 뉴클레오시드가 LNA 뉴클레오시드인, 실시양태 73의 올리고뉴클레오티드.
75. 영역 F 및 F'가 LNA 뉴클레오시드로 이루어지는, 실시양태 74의 올리고뉴클레오티드.
76. 영역 F 및 F'의 모든 변형 뉴클레오시드가 옥시-LNA 뉴클레오시드인, 실시양태 73 내지 75의 올리고뉴클레오티드.
77. 영역 F 또는 F' 중 적어도 하나가 2'-O-알킬-RNA, 2'-O-메틸-RNA, 2'-알콕시-RNA, 2'-O-메톡시에틸-RNA, 2'-아미노-DNA 및 2'-플루오로-DNA로 이루어진 군에서 독립적으로 선택된 2' 치환된 변형 뉴클레오시드를 1개 이상 포함하는, 실시양태 73의 올리고뉴클레오티드.
78. 영역 G의 RNaseH 구성 뉴클레오시드가 DNA, 알파-L-LNA, C4' 알킬화 DNA, ANA 및 2'F-ANA 및 UNA로부터 독립적으로 선택되는, 실시양태 73 내지 77의 올리고뉴클레오티드.
79. 영역 G의 뉴클레오시드가 DNA 및/또는 알파-L-LNA 뉴클레오시드인, 실시양태 78의 올리고뉴클레오티드.
80. 영역 G가 75% 이상의 DNA 뉴클레오시드로 이루어지는, 실시양태 78 또는 79의 올리고뉴클레오티드.
81. 대조군에 비해 UBE3A의 발현을 30% 이상 증가시킬 수 있는, 실시양태 1 내지 80의 올리고뉴클레오티드.
82. SNORD109B 하류의 SNHG14 전사체의 수준이 대조군에 비해 20% 이상 감소되는, 실시양태 1 내지 81의 올리고뉴클레오티드.
83. SNORD115의 발현이 대조군에 비해 유의미하게 영향받지 않는, 실시양태 1 내지 82의 올리고뉴클레오티드.
84. CMP 번호 4_1 내지 678_1로부터 선택되는, 실시양태 1 내지 83의 올리고뉴클레오티드.
85. 다음으로 이루어진 군에서 선택되는, 실시양태 1 내지 83의 올리고뉴클레오티드: CMP 번호 4_1, 4_2, 5_1, 5_2, 6_1, 6_2, 7_1, 7_2, 8_1, 9_1, 10_1, 11_1, 11_2, 12_1, 12_2, 13_1, 13_2, 14_1, 15_1, 16_1, 17_1, 17_2, 18_1, 18_2, 19_1, 19_2, 20_1, 21_1, 22_1, 23_1, 23_2, 24_1, 25_1, 26_1, 26_2, 27_1, 28_1, 28_2, 29_1, 29_2, 30_1, 31_1, 31_2, 32_1, 33_1, 34_1, 34_2, 34_3, 34_4, 34_5, 34_6, 34_7, 35_1, 35_2, 36_1, 37_1, 38_1, 38_2, 38_3, 38_4, 38_5, 38_6, 39_1, 39_2, 39_3, 39_4, 39_5, 40_1, 40_2, 40_3, 40_4, 40_5, 40_6, 40_7, 40_8, 41_1, 42_1, 43_1, 44_1, 44_2, 45_1, 45_2, 46_1, 47_1, 48_1, 48_2, 48_3, 48_4, 48_5, 48_6, 48_7, 49_1, 50_1, 51_1, 52_1, 53_1, 53_2, 54_1, 54_2, 54_3, 55_1, 55_2, 56_1, 57_1, 58_1, 58_2, 58_3, 59_1, 59_2, 60_1, 60_2, 60_3, 61_1, 62_1, 63_1, 64_1, 64_2, 65_1, 66_1, 67_1, 68_1, 69_1, 69_2, 69_3, 70_1, 70_2, 70_3, 71_1, 72_1, 72_2, 73_1, 73_2, 73_3, 74_1, 74_2, 75_1, 75_2, 76_1, 77_1, 77_2, 77_3, 78_1, 79_1, 79_2, 79_3, 80_1, 80_2, 80_3, 81_1, 82_1, 82_2, 83_1, 83_2, 84_1, 84_2, 85_1, 85_2, 86_1, 87_1, 88_1, 88_2, 89_1, 90_1, 91_1, 92_1, 93_1, 94_1, 95_1, 95_2, 96_1, 96_2, 96_3, 97_1, 97_2, 97_3, 97_4, 98_1, 98_2, 98_3, 99_1, 99_2, 99_3, 99_4, 100_1, 100_2, 100_3, 101_1, 101_2, 101_3, 101_4, 102_1, 102_2, 102_3, 102_4, 103_1, 103_2, 103_3, 103_4, 104_1, 104_2, 104_3, 105_1, 105_2, 105_3, 105_4, 106_1, 106_2, 106_3, 106_4, 107_1, 107_2, 107_3, 107_4, 108_1, 108_2, 108_3, 108_4, 109_1, 109_2, 109_3, 109_4, 110_1, 110_2, 111_1, 111_2, 111_3, 112_1, 112_2, 113_1, 114_1, 115_1, 116_1, 117_1, 118_1, 119_1, 120_1, 120_2, 121_1, 122_1, 123_1, 124_1, 125_1, 126_1, 126_2, 127_1, 128_1, 128_2, 128_3, 128_4, 129_1, 129_2, 130_1, 131_1, 132_1, 132_2, 132_3, 133_1, 133_2, 133_3, 133_4, 134_1, 134_2, 135_1, 135_2, 136_1, 137_1, 138_1, 139_1, 140_1, 141_1, 142_1, 143_1, 144_1, 145_1, 145_2, 146_1, 146_2, 147_1, 148_1, 149_1, 150_1, 150_2, 151_1, 152_1, 153_1, 154_1, 155_1, 156_1, 157_1, 158_1, 159_1, 160_1, 161_1, 162_1, 163_1, 164_1, 165_1, 166_1, 167_1, 168_1, 169_1, 169_10, 169_11, 169_12, 169_13, 169_14, 169_15, 169_16, 169_17, 169_18, 169_19, 169_2, 169_20, 169_21, 169_22, 169_23, 169_24, 169_25, 169_26, 169_27, 169_28, 169_29, 169_3, 169_30, 169_31, 169_32, 169_33, 169_34, 169_35, 169_36, 169_37, 169_38, 169_39, 169_4, 169_40, 169_41, 169_42, 169_43, 169_44, 169_45, 169_46, 169_47, 169_48, 169_49, 169_5, 169_50, 169_51, 169_52, 169_53, 169_54, 169_55, 169_56, 169_57, 169_6, 169_7, 169_8, 169_9, 169_58, 169_59, 169_60, 169_61, 169_62, 170_1, 171_1, 172_1, 173_1, 174_1, 175_1, 176_1, 177_1, 178_1, 179_1, 180_1, 181_1, 182_1, 183_1, 184_1, 185_1, 186_1, 187_1, 188_1, 189_1, 190_1, 191_1, 192_1, 193_1, 194_1, 195_1, 196_1, 197_1, 198_1, 199_1, 200_1, 201_1, 202_1, 203_1, 204_1, 205_1, 206_1, 207_1, 208_1, 208_2, 208_3, 208_4, 208_5, 208_6, 208_7, 209_1, 209_10, 209_2, 209_3, 209_4, 209_5, 209_6, 209_7, 209_8, 209_9, 210_1, 211_1, 212_1, 213_1, 214_1, 215_1, 216_1, 217_1, 218_1, 219_1, 220_1, 221_1, 222_1, 223_1, 224_1, 225_1, 226_1, 227_1, 228_1, 229_1, 230_1, 231_1, 232_1, 233_1, 234_1, 235_1, 236_1, 236_10, 236_11, 236_12, 236_13, 236_14, 236_15, 236_16, 236_2, 236_3, 236_4, 236_5, 236_6, 236_7, 236_8, 236_9, 236_17, 236_18, 236_19, 236_20, 236_21, 237_1, 237_10, 237_11, 237_12, 237_13, 237_14, 237_15, 237_16, 237_2, 237_3, 237_4, 237_5, 237_6, 237_7, 237_8, 237_9, 237_17, 237_18, 237_19, 237_20, 237_21, 238_1, 239_1, 239_10, 239_11, 239_12, 239_13, 239_14, 239_15, 239_16, 239_2, 239_3, 239_4, 239_5, 239_6, 239_7, 239_8, 239_9, 239_17, 239_18, 239_19, 239_20, 239_21, 240_1, 241_1, 241_10, 241_2, 241_3, 241_4, 241_5, 241_6, 241_7, 241_8, 241_9, 241_11, 241_12, 241_13, 241_14, 241_15, 242_1, 243_1, 244_1, 244_2, 244_3, 244_4, 244_5, 245_1, 246_1, 247_1, 248_1, 249_1, 250_1, 251_1, 252_1, 253_1, 254_1, 255_1, 256_1, 257_1, 258_1, 259_1, 260_1, 261_1, 262_1, 263_1, 264_1, 265_1, 266_1, 267_1, 268_1, 269_1, 270_1, 271_1, 272_1, 273_1, 274_1, 275_1, 276_1, 277_1, 278_1, 279_1, 280_1, 281_1, 282_1, 283_1, 284_1, 285_1, 285_2, 285_3, 285_4, 285_5, 285_6, 285_7, 285_8, 285_9, 285_10, 285_11, 286_1, 287_1, 288_1, 289_1, 290_1, 291_1, 292_1, 293_1, 294_1, 295_1, 296_1, 297_1, 298_1, 299_1, 300_1, 301_1, 302_1, 303_1, 304_1, 304_10, 304_2, 304_3, 304_4, 304_5, 304_6, 304_7, 304_8, 304_9, 304_11, 304_12, 304_13, 304_14, 304_15, 305_1, 306_1, 307_1, 308_1, 309_1, 310_1, 311_1, 312_1, 313_1, 314_1, 315_1, 316_1, 317_1, 318_1, 319_1, 320_1, 321_1, 322_1, 323_1, 324_1, 325_1, 326_1, 327_1, 328_1, 329_1, 330_1, 331_1, 332_1, 333_1, 334_1, 335_1, 336_1, 337_1, 338_1, 339_1, 340_1, 341_1, 342_1, 343_1, 344_1, 345_1, 346_1, 347_1, 348_1, 349_1, 350_1, 351_1, 352_1, 353_1, 354_1, 355_1, 356_1, 357_1, 358_1, 359_1, 360_1, 361_1, 361_10, 361_2, 361_3, 361_4, 361_5, 361_6, 361_7, 361_8, 361_9, 362_1, 362_10, 362_2, 362_3, 362_4, 362_5, 362_6, 362_7, 362_8, 362_9, 363_1, 364_1, 365_1, 366_1, 367_1, 368_1, 369_1, 370_1, 371_1, 372_1, 373_1, 374_1, 375_1, 376_1, 377_1, 378_1, 379_1, 380_1, 381_1, 382_1, 383_1, 384_1, 385_1, 386_1, 387_1, 388_1, 389_1, 390_1, 391_1, 392_1, 393_1, 394_1, 395_1, 396_1, 397_1, 398_1, 399_1, 400_1, 401_1, 402_1, 403_1, 404_1, 405_1, 406_1, 407_1, 408_1, 409_1, 410_1, 411_1, 412_1, 413_1, 414_1, 415_1, 416_1, 417_1, 418_1, 419_1, 420_1, 421_1, 422_1, 423_1, 424_1, 425_1, 425_10, 425_2, 425_3, 425_4, 425_5, 425_6, 425_7, 425_8, 425_9, 426_1, 427_1, 428_1, 429_1, 430_1, 431_1, 432_1, 433_1, 434_1, 435_1, 436_1, 437_1, 438_1, 439_1, 440_1, 441_1, 442_1, 443_1, 444_1, 445_1, 446_1, 447_1, 448_1, 449_1, 450_1, 451_1, 452_1, 453_1, 454_1, 455_1, 456_1, 457_1, 458_1, 459_1, 460_1, 461_1, 462_1, 463_1, 464_1, 465_1, 466_1, 467_1, 468_1, 469_1, 470_1, 471_1, 472_1, 473_1, 474_1, 475_1, 476_1, 477_1, 478_1, 479_1, 480_1, 481_1, 482_1, 483_1, 484_1, 485_1, 486_1, 487_1, 488_1, 489_1, 490_1, 491_1, 492_1, 493_1, 494_1, 495_1, 496_1, 497_1, 498_1, 499_1, 500_1, 501_1, 502_1, 503_1, 504_1, 505_1, 506_1, 507_1, 508_1, 509_1, 510_1, 511_1, 512_1, 513_1, 514_1, 515_1, 516_1, 517_1, 518_1, 519_1, 520_1, 521_1, 522_1, 523_1, 524_1, 525_1, 526_1, 527_1, 528_1, 529_1, 530_1, 531_1, 532_1, 533_1, 534_1, 535_1, 536_1, 537_1, 538_1, 539_1, 540_1, 541_1, 542_1, 543_1, 544_1, 545_1, 546_1, 547_1, 548_1, 549_1, 550_1, 551_1, 552_1, 553_1, 554_1, 555_1, 556_1, 557_1, 558_1, 559_1, 560_1, 561_1, 562_1, 563_1, 564_1, 565_1, 566_1, 567_1, 568_1, 569_1, 570_1, 570_2, 570_3, 570_4, 570_5, 570_6, 570_7, 570_8, 570_9, 570_10, 570_11, 570_12, 570_13, 570_14, 571_1, 571_2, 571_3, 571_4, 571_5, 571_6, 571_7, 571_8, 571_9, 571_10, 571_11, 571_12, 571_13, 571_14, 572_1, 572_2, 572_3, 572_4, 572_5, 572_6, 572_7, 572_8, 572_9, 572_10, 572_11, 572_12, 572_13, 572_14, 573_1, 573_2, 573_3, 573_4, 573_5, 573_6, 573_7, 573_8, 573_9, 573_10, 573_11, 573_12, 573_13, 573_14, 574_1, 574_2, 574_3, 574_4, 574_5, 574_6, 574_7, 574_8, 574_9, 574_10, 574_11, 574_12, 574_13, 574_14, 575_1, 575_2, 575_3, 575_4, 575_5, 575_6, 575_7, 575_8, 575_9, 575_10, 575_11, 575_12, 575_13, 575_14, 576_1, 576_2, 576_3, 576_4, 576_5, 576_6, 576_7, 576_8, 576_9, 576_10, 576_11, 576_12, 576_13, 576_14, 577_1, 577_2, 577_3, 577_4, 577_5, 577_6, 577_7, 577_8, 577_9, 577_10, 577_11, 577_12, 577_13, 577_14, 578_1, 578_2, 578_3, 578_4, 578_5, 578_6, 578_7, 578_8, 578_9, 579_1, 579_2, 579_3, 579_4, 579_5, 579_6, 579_7, 579_8, 579_9, 580_1, 580_2, 580_3, 580_4, 580_5, 580_6, 580_7, 580_8, 580_9, 581_1, 581_2, 581_3, 581_4, 581_5, 581_6, 581_7, 581_8, 581_9, 582_1, 582_2, 582_3, 582_4, 582_5, 582_6, 582_7, 582_8, 582_9, 583_1, 583_2, 583_3, 583_4, 583_5, 583_6, 583_7, 583_8, 583_9, 584_1, 584_2, 584_3, 584_4, 584_5, 584_6, 584_7, 584_8, 585_1, 585_2, 585_3, 585_4, 585_5, 585_6, 585_7, 585_8, 585_9, 585_10, 585_11, 585_12, 585_13, 585_14, 586_1, 586_2, 586_3, 586_4, 586_5, 586_6, 586_7, 586_8, 586_9, 586_10, 586_11, 586_12, 586_13, 586_14, 587_1, 587_2, 587_3, 587_4, 587_5, 587_6, 587_7, 587_8, 587_9, 587_10, 587_11, 587_12, 587_13, 587_14, 588_1, 588_2, 588_3, 588_4, 588_5, 588_6, 588_7, 588_8, 588_9, 588_10, 588_11, 588_12, 588_13, 588_14, 589_1, 589_2, 589_3, 589_4, 589_5, 589_6, 589_7, 589_8, 589_9, 589_10, 589_11, 589_12, 589_13, 589_14, 590_1, 590_10, 590_11, 590_12, 590_13, 590_14, 590_15, 590_2, 590_3, 590_4, 590_5, 590_6, 590_7, 590_8, 590_9, 590_16, 590_17, 590_18, 590_19, 590_20, 591_1, 591_2, 592_1, 592_2, 592_3, 592_4, 592_5, 592_6, 592_7, 592_8, 592_9, 592_10, 592_11, 592_12, 592_13, 592_14, 593_1, 593_2, 593_3, 593_4, 594_1, 594_2, 594_3, 594_4, 595_1, 595_2, 595_3, 595_4, 596_1, 596_2, 596_3, 596_4, 597_1, 597_2, 597_3, 597_4, 598_1, 598_2, 598_3, 598_4, 599_1, 599_2, 599_3, 599_4, 600_1, 600_2, 600_3, 600_4, 601_1, 601_2, 601_3, 601_4, 602_1, 602_2, 602_3, 602_4, 603_1, 603_2, 603_3, 603_4, 604_1, 604_2, 604_3, 604_4, 605_1, 605_2, 605_3, 605_4, 606_1, 606_2, 606_3, 606_4, 607_1, 607_2, 607_3, 607_4, 608_1, 608_2, 608_3, 608_4, 608_5, 608_6, 608_7, 608_8, 608_9, 609_1, 609_2, 609_3, 609_4, 609_5, 609_6, 609_7, 609_8, 609_9, 610_1, 610_2, 610_3, 610_4, 610_5, 610_6, 610_7, 610_8, 610_9, 611_1, 611_2, 611_3, 611_4, 611_5, 611_6, 611_7, 611_8, 611_9, 612_1, 612_2, 612_3, 612_4, 612_5, 612_6, 612_7, 612_8, 612_9, 613_1, 613_2, 613_3, 613_4, 613_5, 613_6, 613_7, 613_8, 613_9, 613_10, 614_1, 614_2, 614_3, 614_4, 614_5, 614_6, 614_7, 614_8, 614_9, 614_10, 615_1, 615_2, 615_3, 615_4, 615_5, 615_6, 615_7, 615_8, 615_9, 615_10, 616_1, 616_2, 616_3, 616_4, 616_5, 616_6, 616_7, 616_8, 616_9, 616_10, 617_1, 617_2, 617_3, 617_4, 617_5, 617_6, 617_7, 617_8, 617_9, 617_10, 618_1, 618_2, 618_3, 618_4, 618_5, 618_6, 618_7, 618_8, 618_9, 618_10, 619_1, 619_2, 619_3, 619_4, 619_5, 619_6, 619_7, 619_8, 619_9, 619_10, 620_1, 620_2, 620_3, 620_4, 620_5, 620_6, 620_7, 620_8, 620_9, 620_10, 621_1, 621_2, 621_3, 621_4, 621_5, 621_6, 621_7, 621_8, 621_9, 621_10, 621_11, 622_1, 622_2, 622_3, 622_4, 622_5, 622_6, 622_7, 622_8, 622_9, 622_10, 623_1, 623_2, 623_3, 623_4, 623_5, 623_6, 623_7, 623_8, 623_9, 623_10, 624_1, 624_2, 624_3, 624_4, 624_5, 624_6, 624_7, 624_8, 624_9, 624_10, 625_1, 625_2, 625_3, 625_4, 625_5, 625_6, 625_7, 625_8, 625_9, 625_10, 625_11, 625_12, 625_13, 625_14, 626_1, 626_2, 626_3, 626_4, 626_5, 626_6, 626_7, 626_8, 626_9, 626_10, 626_11, 626_12, 626_13, 626_14, 627_1, 627_2, 627_3, 627_4, 627_5, 627_6, 627_7, 627_8, 627_9, 627_10, 627_11, 627_12, 627_13, 627_14, 628_1, 628_2, 628_3, 628_4, 628_5, 628_6, 628_7, 628_8, 628_9, 628_10, 628_11, 628_12, 628_13, 628_14, 629_1, 629_10, 629_11, 629_2, 629_3, 629_4, 629_5, 629_6, 629_7, 629_8, 629_9, 629_12, 629_13, 629_14, 629_15, 629_16, 630_1, 630_2, 630_3, 631_1, 631_10, 631_2, 631_3, 631_4, 631_5, 631_6, 631_7, 631_8, 631_9, 631_11, 631_12, 631_13, 631_14, 631_15, 632_1, 632_2, 632_3, 632_4, 632_5, 632_6, 632_7, 632_8, 632_9, 632_10, 632_11, 632_12, 632_13, 632_14, 633_1, 633_2, 633_3, 633_4, 633_5, 633_6, 633_7, 633_8, 633_9, 634_1, 634_2, 634_3, 634_4, 634_5, 634_6, 634_7, 634_8, 634_9, 635_1, 635_2, 635_3, 635_4, 635_5, 635_6, 635_7, 635_8, 635_9, 636_1, 636_2, 636_3, 636_4, 636_5, 636_6, 636_7, 636_8, 636_9, 637_1, 637_2, 637_3, 637_4, 637_5, 637_6, 637_7, 637_8, 637_9, 638_1, 638_2, 638_3, 638_4, 638_5, 638_6, 638_7, 638_8, 638_9, 638_10, 638_11, 638_12, 638_13, 638_14, 639_1, 639_2, 639_3, 639_4, 639_5, 639_6, 639_7, 639_8, 639_9, 639_10, 639_11, 639_12, 639_13, 639_14, 640_1, 640_2, 640_3, 640_4, 640_5, 640_6, 640_7, 640_8, 640_9, 640_10, 640_11, 640_12, 640_13, 640_14, 641_1, 641_2, 641_3, 641_4, 641_5, 641_6, 641_7, 641_8, 641_9, 642_1, 642_10, 642_11, 642_12, 642_13, 642_14, 642_15, 642_16, 642_17, 642_2, 642_3, 642_4, 642_5, 642_6, 642_7, 642_8, 642_9, 642_18, 642_19, 642_20, 642_21, 642_22, 643_1, 644_1, 644_2, 644_3, 644_4, 644_5, 644_6, 645_1, 645_2, 645_3, 645_4, 645_5, 645_6, 645_7, 645_8, 645_9, 645_10, 646_1, 646_10, 646_11, 646_12, 646_13, 646_14, 646_15, 646_16, 646_17, 646_18, 646_19, 646_2, 646_3, 646_4, 646_5, 646_6, 646_7, 646_8, 646_9, 646_20, 646_21, 646_22, 646_23, 646_24, 647_1, 648_1, 649_1, 650_1, 651_1, 652_1, 653_1, 654_1, 655_1, 656_1, 657_1, 658_1, 659_1, 660_1, 661_1, 662_1, 663_1, 664_1, 665_1, 666_1, 667_1, 668_1, 669_1, 670_1, 671_1, 672_1, 673_1, 674_1, 675_1, 676_1, 677_1, 678_1, 679_1, 679_2, 679_3, 679_4, 679_5, 680_1, 680_2, 680_3, 680_4, 680_5, 681_1, 681_2, 681_3, 681_4, 681_5, 682_1, 682_2, 682_3, 682_4, 682_5, 683_1, 683_2, 683_3, 683_4, 683_5, 684_1, 684_2, 684_3, 684_4, 684_5, 685_1, 685_2, 685_3, 685_4, 685_5, 686_1, 686_2, 686_3, 686_4, 686_5, 687_1, 687_2, 687_3, 687_4, 687_5, 688_1, 688_2, 688_3, 688_4, 688_5, 689_1, 689_2, 689_3, 689_4, 689_5, 690_1, 690_2, 690_3, 690_4, 690_5, 691_1, 691_2, 692_1, 692_2, 692_3, 692_4, 692_5, 693_1, 693_2, 693_3, 693_4, 693_5, 694_1, 694_2, 694_3, 694_4, 694_5, 695_1, 695_2, 695_3, 695_4, 695_5, 696_1, 696_2, 696_3, 696_4, 696_5, 697_1, 697_2, 697_3, 697_4, 697_5, 698_1, 698_2, 698_3, 698_4, 698_5, 699_1, 699_2, 699_3, 699_4, 699_5, 700_1, 700_2, 700_3, 700_4, 700_5, 701_1, 701_2, 701_3, 701_4, 701_5, 702_1, 702_2, 702_3, 702_4, 702_5, 703_1, 703_2, 703_3, 703_4, 703_5, 704_1, 704_2, 704_3, 704_4, 704_5, 705_1, 705_2, 705_3, 705_4, 705_5, 706_1, 706_2, 706_3, 706_4, 706_5, 707_1, 707_2, 707_3, 707_4, 707_5, 708_1, 708_2, 708_3, 708_4, 708_5, 709_1, 709_2, 709_3, 709_4, 709_5, 710_1, 710_2, 710_3, 710_4, 710_5, 711_1, 711_2, 711_3, 711_4, 711_5, 712_1, 712_2, 712_3, 712_4, 712_5, 713_1, 713_2, 713_3, 713_4, 713_5, 714_1, 714_2, 714_3, 714_4, 714_5, 715_1, 715_2, 715_3, 715_4, 715_5, 716_1, 716_2, 716_3, 716_4, 716_5, 717_1, 717_2, 717_3, 717_4, 717_5, 718_1, 718_2, 719_1, 719_2, 719_3, 719_4, 719_5, 720_1, 720_2, 720_3, 720_4, 720_5, 721_1, 721_2, 721_3, 721_4, 721_5, 722_1, 722_2, 722_3, 722_4, 722_5, 723_1, 723_2, 723_3, 723_4, 723_5, 724_1, 724_2, 724_3, 724_4, 724_5, 725_1, 725_2, 725_3, 725_4, 725_5, 726_1, 726_2, 726_3, 726_4, 726_5, 727_1, 727_2, 727_3, 727_4, 727_5, 728_1, 728_2, 728_3, 728_4, 728_5, 729_1, 729_2, 729_3, 729_4, 729_5, 730_1, 730_2, 730_3, 730_4, 730_5, 731_1, 731_2, 731_3, 731_4, 731_5, 732_1, 732_2, 732_3, 732_4, 732_5, 733_1, 733_2, 733_3, 733_4, 733_5, 734_1, 734_2, 734_3, 734_4, 734_5, 735_1, 735_2, 735_3, 735_4, 735_5, 736_1, 736_2, 736_3, 736_4, 736_5, 737_1, 737_2, 737_3, 737_4, 737_5, 738_1, 738_2, 738_3, 738_4, 738_5, 738_6, 739_1, 739_2, 739_3, 739_4, 739_5, 740_1, 740_2, 740_3, 740_4, 740_5, 741_1, 741_2, 741_3, 741_4, 741_5, 742_1, 742_2, 742_3, 743_1, 743_2, 743_3, 743_4, 743_5, 744_1, 744_2, 744_3, 744_4, 744_5, 745_1, 745_2, 745_3, 745_4, 745_5, 746_1, 746_2, 746_3, 747_1, 747_2, 747_3, 747_4, 747_5, 748_1, 748_2, 748_3, 748_4, 748_5, 749_1, 749_2, 749_3, 749_4, 749_5, 750_1, 750_2, 750_3, 750_4, 751_1, 751_2, 751_3, 751_4, 751_5, 752_1, 752_2, 752_3, 752_4, 752_5, 753_1, 753_2, 753_3, 753_4, 753_5, 754_1, 754_2, 754_3, 754_4, 754_5, 755_1, 755_2, 755_3, 755_4, 755_5, 756_1, 756_2, 756_3, 756_4, 756_5, 757_1, 757_2, 757_3, 757_4, 757_5, 758_1, 758_2, 758_3, 758_4, 758_5, 759_1, 759_2, 759_3, 759_4, 759_5, 760_1, 760_2, 760_3, 760_4, 760_5, 761_1, 761_2, 761_3, 761_4, 761_5, 762_1, 762_2, 762_3, 762_4, 762_5, 763_1, 763_2, 763_3, 763_4, 763_5, 764_1, 764_2, 764_3, 764_4, 764_5, 765_1, 765_2, 765_3, 765_4, 765_5, 766_1, 766_2, 766_3, 766_4, 766_5, 767_1, 767_2, 767_3, 767_4, 767_5, 768_1, 768_2, 768_3, 768_4, 768_5, 769_1, 769_2, 769_3, 769_4, 769_5, 770_1, 770_2, 770_3, 770_4, 770_5, 771_1, 771_2, 771_3, 771_4, 771_5, 772_1, 772_2, 772_3, 772_4, 772_5, 773_1, 773_2, 773_3, 773_4, 773_5, 774_1, 774_2, 774_3, 774_4, 774_5, 775_1, 775_2, 775_3, 775_4, 775_5, 776_1, 776_2, 776_3, 776_4, 776_5, 777_1, 777_2, 777_3, 777_4, 777_5, 778_1, 778_2, 778_3, 778_4, 778_5, 779_1, 779_2, 779_3, 779_4, 779_5, 780_1, 780_2, 780_3, 780_4, 780_5, 781_1, 782_1, 782_2, 782_3, 782_4, 782_5, 783_1, 783_2, 783_3, 783_4, 783_5, 784_1, 784_2, 784_3, 784_4, 784_5, 785_1, 786_1, 786_2, 786_3, 786_4, 786_5, 787_1, 787_2, 787_3, 787_4, 787_5, 788_1, 788_2, 788_3, 788_4, 788_5, 789_1, 789_2, 789_3, 789_4, 789_5, 790_1, 790_2, 790_3, 790_4, 790_5, 791_1, 791_2, 791_3, 791_4, 791_5, 792_1, 792_2, 792_3, 792_4, 792_5, 793_1, 793_2, 793_3, 793_4, 793_5, 794_1, 794_2, 794_3, 794_4, 794_5, 795_1, 795_2, 795_3, 795_4, 795_5, 796_1, 796_2, 796_3, 796_4, 796_5, 797_1, 797_2, 797_3, 797_4, 797_5, 798_1, 798_2, 798_3, 798_4, 798_5, 799_1, 799_2, 799_3, 799_4, 799_5, 800_1, 800_2, 800_3, 800_4, 800_5, 801_1, 801_2, 801_3, 801_4, 801_5, 802_1, 802_2, 802_3, 802_4, 802_5, 803_1, 803_2, 803_3, 803_4, 803_5, 804_1, 804_2, 804_3, 804_4, 804_5, 805_1, 805_2, 805_3, 805_4, 805_5, 806_1, 806_2, 806_3, 806_4, 806_5, 807_1, 807_2, 807_3, 807_4, 807_5, 808_1, 808_2, 808_3, 808_4, 808_5, 809_1, 809_2, 809_3, 809_4, 809_5, 810_1, 810_2, 810_3, 810_4, 810_5, 811_1, 811_2, 811_3, 811_4, 811_5, 812_1, 812_2, 812_3, 812_4, 812_5, 813_1, 813_2, 813_3, 813_4, 813_5, 814_1, 814_2, 814_3, 814_4, 814_5, 815_1, 815_2, 815_3, 815_4, 815_5, 816_1, 816_2, 816_3, 816_4, 816_5, 816_6, 817_1 및 818_1.
86. CMP 번호 155_1 또는 165_1로부터 선택되는, 실시양태 85의 올리고뉴클레오티드.
87. CMP 번호 169_52, 169_50 또는 169_56으로 이루어진 군에서 선택되는, 실시양태 85의 올리고뉴클레오티드.
88. CMP 번호 172_1, 272_1, 572_7, 572_6 또는 572_5로 이루어진 군에서 선택되는, 실시양태 85의 올리고뉴클레오티드.
89. CMP 번호 175_1로부터 선택되는, 실시양태 85의 올리고뉴클레오티드.
90. CMP 번호 178_1로부터 선택되는, 실시양태 85의 올리고뉴클레오티드.
91. CMP 번호 573_8, 186_1 또는 187_1로부터 선택되는, 실시양태 85의 올리고뉴클레오티드.
92. CMP 번호 186_1로부터 선택되는, 실시양태 85의 올리고뉴클레오티드.
93. CMP 번호 200_1, 204_1, 206_1, 35_2 또는 209_1로 이루어진 군에서 선택되는, 실시양태 85의 올리고뉴클레오티드.
94. CMP 번호 585_1, 585_8, 586_9, 586_5, 586_8, 586_4 또는 586_6으로 이루어진 군에서 선택되는, 실시양태 85의 올리고뉴클레오티드.
95. CMP 번호 233_1로부터 선택되는, 실시양태 85의 올리고뉴클레오티드.
96. CMP 번호 237_8 또는 590_13으로부터 선택되는, 실시양태 85의 올리고뉴클레오티드.
97. CMP 번호 220_1로부터 선택되는, 실시양태 85의 올리고뉴클레오티드.
98. CMP 번호 591_1, 592_2, 592_4 또는 241_9로 이루어진 군에서 선택되는, 실시양태 85의 올리고뉴클레오티드.
99. CMP 번호 597_4, 598_4, 39_1 또는 602_1로 이루어진 군에서 선택되는, 실시양태 85의 올리고뉴클레오티드.
100. CMP 번호 39_1로부터 선택되는, 실시양태 85의 올리고뉴클레오티드.
101. CMP 번호 611_7로부터 선택되는, 실시양태 85의 올리고뉴클레오티드.
102. CMP 번호 271_1 또는 278_1로 이루어진 군에서 선택되는, 실시양태 85의 올리고뉴클레오티드.
103. CMP 번호 616_4, 621_2, 621_1, 622_3, 622_5, 622_4, 624_3, 624_5, 287_1, 625_6, 626_7, 626_8, 626_9, 48_1, 631_6, 631_1, 303_1, 304_6 또는 304_10으로 이루어진 군에서 선택되는, 실시양태 85의 올리고뉴클레오티드.
104. CMP 번호 636_8로부터 선택되는, 실시양태 85의 올리고뉴클레오티드.
105. CMP 번호 638_8, 639_5, 331_1 또는 640_4로 이루어진 군에서 선택되는, 실시양태 85의 올리고뉴클레오티드.
106. CMP 번호 359_1, 361_1, 361_5, 362_1 또는 641_5로 이루어진 군에서 선택되는, 실시양태 85의 올리고뉴클레오티드.
107. CMP 번호 378_1, 379_1 또는 399_1로 이루어진 군에서 선택되는, 실시양태 85의 올리고뉴클레오티드.
108. CMP 번호 403_1, 405_1, 642_12, 642_13, 644_3 또는 646_16으로 이루어진 군에서 선택되는, 실시양태 85의 올리고뉴클레오티드.
109. CMP 번호 85_1 또는 425_5로부터 선택되는, 실시양태 85의 올리고뉴클레오티드.
110. CMP 번호 116_1로부터 선택되는, 실시양태 85의 올리고뉴클레오티드.
111. CMP 번호 123_1 또는 124_1로부터 선택되는, 실시양태 85의 올리고뉴클레오티드.
112. CMP 번호 126_2로부터 선택되는, 실시양태 85의 올리고뉴클레오티드.
113. 1개 이상의 접합체 잔기가 공유적으로 결합된, 실시양태 1 내지 112 중 어느 하나에 따른 올리고뉴클레오티드를 포함하는 접합체.
114. 접합체 잔기가 탄수화물, 세포 표면 수용체 리간드, 약물 물질, 호르몬, 친유성 물질, 중합체, 단백질, 펩티드, 독소, 비타민, 바이러스 단백질 또는 그의 조합으로부터 선택되는, 실시양태 113의 올리고뉴클레오티드 접합체.
115. 접합체 잔기가 항체 또는 항체 단편인, 실시양태 113 또는 114의 올리고뉴클레오티드 접합체.
116. 항체 또는 항체 단편이 트랜스페린 수용체에 대한 친화성을 갖는, 실시양태 115의 올리고뉴클레오티드 접합체.
117. 올리고뉴클레오티드와 접합체 잔기 사이에 위치한 링커를 포함하는, 실시양태 113 내지 115의 올리고뉴클레오티드 접합체.
118. 링커가 생리적으로 불안정한 링커인, 실시양태 117의 올리고뉴클레오티드 접합체.
119. 생리적으로 불안정한 링커가 뉴클레아제 민감성 링커인, 실시양태 118의 올리고뉴클레오티드 접합체.
120. 올리고뉴클레오티드가 식 D-F-G-F' 또는 F-G-F'-D'를 가지며, 이때 F, F' 및 G는 실시양태 73 내지 80에서 정의된 바와 같고 D 또는 D'는 포스포로티오에이트 뉴클레오시드간 결합하에 1, 2 또는 3개의 DNA 뉴클레오시드를 포함하는, 실시양태 118 또는 119의 올리고뉴클레오티드 접합체.
121. 비접합 올리고뉴클레오티드에 비해 접합체 올리고뉴클레오티드의 개선된 뇌내 흡수를 나타내는, 실시양태 113 내지 120의 올리고뉴클레오티드 접합체.
122. 실시양태 1 내지 112의 올리고뉴클레오티드 또는 실시양태 113 내지 121의 접합체 및 약학적으로 허용되는 희석제, 담체, 염 및/또는 보조제를 포함하는 약학 조성물.
123. 뉴클레오티드 단위들을 반응시켜 올리고뉴클레오티드에 포함되는 공유 결합된 연속 뉴클레오티드 단위를 생성하는 것을 포함하는, 실시양태 1 내지 112의 올리고뉴클레오티드의 제조 방법.
124. 연속 뉴클레오티드 서열을 비-뉴클레오티드 접합 잔기와 반응시키는 것을 추가로 포함하는, 실시양태 123의 방법.
125. 올리고뉴클레오티드를 약학적으로 허용되는 희석제, 담체, 염 및/또는 보조제와 혼합하는 것을 포함하는, 실시양태 122의 조성물의 제조 방법.
126. 실시양태 1 내지 112 중 어느 하나의 올리고뉴클레오티드 또는 실시양태 113 내지 121의 접합체 또는 실시양태 122의 약학 조성물을 효과량으로 표적 세포에 투여하는 것을 포함하는, 부계 UBE3A의 발현이 억제되는 표적 세포에서 UBE3A 발현을 유도하기 위한 생체내 또는 시험관내 방법.
127. UBE3A의 발현이 대조군에 비해 40% 이상 증가되는, 실시양태 126의 방법.
128. SNORD109B 하류의 SNHG14 전사체의 수준이 대조군에 비해 30% 이상 감소되는, 실시양태 126 또는 127의 방법.
129. 표적 세포가 뉴런 세포인, 실시양태 126 내지 128의 방법.
130. SNORD115의 발현이 대조군에 비해 유의미하게 영향받지 않는, 실시양태 126 내지 129의 방법.
131. 치료 또는 예방 효과량의 실시양태 1 내지 112의 올리고뉴클레오티드 또는 실시양태 113 내지 121의 접합체 또는 실시양태 122의 약학 조성물을 질환을 앓고 있거나 질환에 걸리기 쉬운 대상에게 투여하는 것을 포함하는, 질환을 치료 또는 예방하는 방법.
132. 대상에서 질환의 치료 또는 예방을 위한 약제로서 사용하기 위한, 실시양태 1 내지 112의 올리고뉴클레오티드 또는 실시양태 113 내지 121의 접합체 또는 실시양태 122의 약학 조성물.
133. 대상에서 질환의 치료 또는 예방을 위한 약제의 제조를 위한, 실시양태 1 내지 112의 올리고뉴클레오티드 또는 실시양태 113 내지 121의 접합체의 용도.
134. 질환이 UBE3A의 생체내 활성과 연관되는, 실시양태 131 내지 133의 방법, 올리고뉴클레오티드 또는 용도.
135. 질환이 뉴런 세포에서 UBE3A의 감소된 발현 및/또는 UBE3A의 감소된 활성과 연관되는, 실시양태 131 내지 134의 방법, 올리고뉴클레오티드 또는 용도.
136. UBE3A의 감소된 발현 및/또는 UBE3A의 감소된 활성이 UBE3A 유전자의 모계 대립유전자에서의 돌연변이에 기인하는, 실시양태 135의 방법, 올리고뉴클레오티드 또는 용도.
137. UBE3A 발현이, 실시양태 1 내지 112의 올리고뉴클레오티드 또는 실시양태 113 내지 121의 접합체 또는 실시양태 122의 약학 조성물의 부재하에서의 발현에 비해, 30% 이상, 또는 50% 이상, 또는 70% 이상, 또는 90% 이상, 또는 100% 이상, 또는 150% 이상, 또는 200% 이상 증가되는, 실시양태 134 내지 136의 방법, 올리고뉴클레오티드 또는 용도.
138. 질환이 엔젤만 증후군인, 실시양태 131 내지 137의 방법, 올리고뉴클레오티드 또는 용도.
139. 대상이 포유동물인, 실시양태 131 내지 138의 방법, 올리고뉴클레오티드 또는 용도.
140. 포유동물이 인간인, 실시양태 139의 방법, 올리고뉴클레오티드 또는 용도.
141. 대상이 유아 또는 청소년인, 실시양태 139 또는 140의 방법, 올리고뉴클레오티드 또는 용도.
실시예
재료 및 방법
[표 3]
서열번호 1에 상보적인 올리고뉴클레오티드 또는 연속 핵염기 서열들(서열번호로 나타낸 모티프 서열들), 이들로부터 제조된 올리고뉴클레오티드 디자인뿐 아니라 모티프 서열에 기반하여 설계된 특정 올리고뉴클레오티드 화합물(CMP 번호로 나타냄)의 목록
Figure 112020127052610-pat00041
Figure 112020127052610-pat00042
Figure 112020127052610-pat00043
Figure 112020127052610-pat00044
Figure 112020127052610-pat00045
Figure 112020127052610-pat00046
Figure 112020127052610-pat00047
Figure 112020127052610-pat00048
Figure 112020127052610-pat00049
Figure 112020127052610-pat00050
Figure 112020127052610-pat00051
Figure 112020127052610-pat00052
Figure 112020127052610-pat00053
Figure 112020127052610-pat00054
Figure 112020127052610-pat00055
Figure 112020127052610-pat00056
Figure 112020127052610-pat00057
Figure 112020127052610-pat00058
Figure 112020127052610-pat00059
Figure 112020127052610-pat00060
Figure 112020127052610-pat00061
Figure 112020127052610-pat00062
Figure 112020127052610-pat00063
Figure 112020127052610-pat00064
Figure 112020127052610-pat00065
Figure 112020127052610-pat00066
Figure 112020127052610-pat00067
Figure 112020127052610-pat00068
Figure 112020127052610-pat00069
Figure 112020127052610-pat00070
Figure 112020127052610-pat00071
Figure 112020127052610-pat00072
Figure 112020127052610-pat00073
Figure 112020127052610-pat00074
Figure 112020127052610-pat00075
Figure 112020127052610-pat00076
Figure 112020127052610-pat00077
Figure 112020127052610-pat00078
Figure 112020127052610-pat00079
Figure 112020127052610-pat00080
Figure 112020127052610-pat00081
Figure 112020127052610-pat00082
Figure 112020127052610-pat00083
Figure 112020127052610-pat00084
Figure 112020127052610-pat00085
Figure 112020127052610-pat00086
Figure 112020127052610-pat00087
Figure 112020127052610-pat00088
Figure 112020127052610-pat00089
Figure 112020127052610-pat00090
Figure 112020127052610-pat00091
Figure 112020127052610-pat00092
Figure 112020127052610-pat00093
Figure 112020127052610-pat00094
Figure 112020127052610-pat00095
Figure 112020127052610-pat00096
Figure 112020127052610-pat00097
Figure 112020127052610-pat00098
Figure 112020127052610-pat00099
Figure 112020127052610-pat00100
Figure 112020127052610-pat00101
Figure 112020127052610-pat00102
Figure 112020127052610-pat00103
Figure 112020127052610-pat00104
Figure 112020127052610-pat00105
Figure 112020127052610-pat00106
Figure 112020127052610-pat00107
Figure 112020127052610-pat00108
Figure 112020127052610-pat00109
Figure 112020127052610-pat00110
Figure 112020127052610-pat00111
Figure 112020127052610-pat00112
Figure 112020127052610-pat00113
Figure 112020127052610-pat00114
Figure 112020127052610-pat00115
Figure 112020127052610-pat00116
Figure 112020127052610-pat00117
Figure 112020127052610-pat00118
Figure 112020127052610-pat00119
Figure 112020127052610-pat00120
Figure 112020127052610-pat00121
디자인은 갭머 디자인, F-G-F'를 말하고, 이때 각 숫자는 연속 변형 뉴클레오시드, 예를 들면, 2' 변형 뉴클레오시드의 수(첫번째 숫자 = 5' 측면서열)에 이어, DNA 뉴클레오시드의 수(두번째 숫자 = 갭 영역)에 이어, 변형 뉴클레오시드, 예를 들어, 2' 변형 뉴클레오시드의 수(세번째 숫자 = 3' 측면서열)를 나타내며, 선택적으로, 반드시 표적 핵산에 상보적인 연속 서열 부분은 아닌 또 다른 DNA 및 LNA의 반복 영역이 그 앞에 오거나 그 뒤에 온다. 표 3에서 일부 올리고뉴클레오티드의 경우, 측면서열들은 혼합된 측면서열들이며, 상기 측면서열들은 2' 변형 뉴클레오시드로 시작하고 끝나며, 이 경우 갭 영역은 디자인의 5' 또는 3' 말단에 위치하지 않은, 5보다 높은 수이다.
올리고뉴클레오티드 화합물의 경우, 대문자는 베타-D-옥시 LNA 뉴클레오시드를 나타내고, 소문자는 DNA 뉴클레오시드를 나타내고, 모든 LNA C는 5-메틸 시토신이고, 5-메틸 DNA 시토신은 "e"로 나타내고, 모든 뉴클레오시드간 결합은 포스포로티오에이트 뉴클레오시드간 결합이다.
서열번호 1 위에 출발로서 EX-EX 표시를 갖는 올리고뉴클레오티드는 SNHG14-023(ENST00000554726)의 엑손-엑손 접합부 전체에 걸쳐 상보적이도록 설계된 엑손-엑손에 걸친 올리고뉴클레오티드이다. 상기 올리고뉴클레오티드는 주로 엑손2 및 엑손3에 걸쳐있다(즉, 엑손2의 영역 및 엑손 3의 영역에 상보적이다).
올리고뉴클레오티드 합성
올리고뉴클레오티드 합성은 일반적으로 당해 분야에 공지되어 있다. 하기는 적용될 수 있는 프로토콜이다. 본 발명의 올리고뉴클레오티드는 사용된 장치, 지지체 및 농도의 측면에서 약간 달라지는 방법에 의해 생성되었을 수 있다.
올리고뉴클레오티드는 머메이드(MerMade)12 또는 올리고메이커(Oligomaker) DNA/RNA 합성기 상에서 1 내지 4 μM 규모로 포스포르아미다이트 접근방법을 이용하여 우리딘 범용 지지체 상에서 합성하였다. 합성 마지막에, 올리고뉴클레오티드는 60 ℃에서 5 내지 16 시간동안 수성 암모니아를 사용하여 고체 지지체로부터 분리된다. 올리고뉴클레오티드는 역상 HPLC(RP-HPLC)에 의해 또는 고체상 추출에 의해 정제되고 UPLC에 의해 특성화되고, 분자 질량도 또한 ESI-MS에 의해 확인된다.
올리고뉴클레오티드의 연장:
β-시아노에틸-포스포르아미다이트(DNA-A(Bz), DNA-G(ibu), DNA-C(Bz), DNA-T, LNA-5-메틸-C(Bz), LNA-A(Bz), LNA-G(dmf), LNA-T 또는 아미노-C6 링커)의 커플링은 아세토니트릴 중의 0.1 M의 5'-O-DMT-보호된 아미다이트의 용액 및 활성화제로서 아세토니트릴(0.25 M) 중의 DCI(4,5-다이시아노이미다졸)를 사용하여 수행한다. 최종 주기동안, 목적하는 변형을 갖는 포스포르아미다이트, 예를 들면, 접합체 기를 결합시키기 위한 C6 링커 또는 접합체 기 자체를 사용할 수 있다. 포스포르티오에이트 결합의 도입을 위한 티올화는 잔탄 하이드라이드(아세토니트릴/피리딘 9:1 중의 0.01 M)를 사용하여 수행한다. 포스포르다이에스터 결합은 THF/피리딘/물 7:2:1 중의 0.02 M 요오드를 사용하여 도입될 수 있다. 나머지 시약들은 올리고뉴클레오티드 합성에 전형적으로 사용되는 것들이다.
RP-HPLC에 의한 정제:
조화합물들은 페노메넥스 주피터(Phenomenex Jupiter) C18 10μ 150x10 mm 컬럼 상에서 예비 RP-HPLC에 의해 정제된다. 0.1 M 암모늄 아세테이트(pH 8) 및 아세토니트릴이 완충액으로서 5 mL/분의 유량으로 사용된다. 수집된 분획들을 동결건조시켜 정제된 화합물을 전형적으로 백색 고체로서 수득한다.
약자:
DCI: 4,5-다이시아노이미다졸
DCM: 다이클로로메탄
DMF: 다이메틸폼아미드
DMT: 4,4'-다이메톡시트리틸
THF: 테트라하이드푸란
Bz: 벤조일
Ibu: 이소부티릴
RP-HPLC: 역상 고성능 액체 크로마토그래피
T m 분석
올리고뉴클레오티드와 RNA 표적 이중체를 500 ml RNase-비함유수에 3 mM로 희석하고 500 ml 2x Tm-완충액(200 mM NaCl, 0.2 mM EDTA, 20 mM Na포스페이트, pH 7.0)과 혼합한다. 용액을 3 분동안 95 ℃로 가열한 다음 실온에서 30 분동안 어닐링시킨다. 이중체 용융 온도(Tm)는, PE 템프랩(Templab) 소프트웨어(퍼킨 엘머(Perkin Elmer))를 사용하여 펠타이어(Peltier) 온도 프로그래머 PTP6이 장착된 람다(Lambda) 40 UV/VIS 분광광도계 상에서 측정한다. 온도를 20 ℃에서 95 ℃로 상승시킨 다음 25 ℃로 저하시켜 260 nm에서의 흡광도를 기록한다. 용융 및 어닐링 둘 다의 1차 도함수 및 극댓값을 이용하여 이중체 Tm을 평가한다.
마우스 1차 피질 뉴런 세포 배양물의 제조
1차 피질 뉴런 배양물을 표준 절차에 따라서 15 일된 마우스 배아 뇌로부터 제조하였다. 간략하게, 배양 플레이트를 실온에서 폴리-L-라이신(50 ㎍/ml 폴리-L-라이신, 10 mM Na-테트라보레이트, pH 8 완충액)으로 2 내지 3 시간동안 코팅하였다. 플레이트를 사용전에 1xPBS로 세척하였다. 수거된 마우스 배아 뇌를 면도날로 해부하고 균질화시키고 38 ml 해부 배지(HBSS, 0.01 M Hepes, 페니실린(Penicillin)/스트렙토마이신(Streptomycin))에 침지시켰다. 이어서, 2 ml 트립신을 첨가하고 세포를 37 ℃에서 30 분동안 배양하고 원심분리하였다. 세포를 20 ml DMEM (+ 10% FBS)에 용해시키고 추가의 균질화를 위해 주사기에 통과시켰다. 그 다음 500 rpm에서 15 분동안 원심분리하였다. 세포를 DMEM(+10% FBS)에 용해시키고 96 웰 플레이트에 접종하였다(100 ㎕ 중 0.1 x 10^6 세포/웰). 뉴런 세포 배양물은 접종후 바로 사용하도록 준비하였다.
마우스 1차 피질 뉴런 세포 배양물 중 올리고뉴클레오티드의 스크리닝
세포를 96-웰 플레이트에서 성장 배지(깁코 신경세포배양용 배지(Gibco Neurobasal medium), B27 보충제, 글루타맥스(Glutamax), 페니실린-스트렙토마이신)에서 배양하고 목적하는 농도에서 3 일동안 올리고뉴클레오티드와 함께 배양하였다. 전체 RNA를 세포로부터 단리하고, 콴타 바이오사이언스(Quanta Bioscience)의 qScript™ XLT 원-스텝 RT-qPCR 터프믹스(ToughMix)®, 로우 록스(Low ROX)™ 키트(95134-500)를 사용하여 qPCR 분석에 의해 녹다운(knock-down) 효능을 측정하였다. 터모 피셔 사이언티픽(Thermo Fisher Scientific)으로부터의 상업적 태크맨(taqman) 분석을 이용하여 표준화를 위한 GAPDH를 포함한 Ube3a_ATS를 측정하였다.
인간 1차 뉴런 세포 배양물의 생성
임의의 기술된 시점에서 임의의 세포주를 37 ℃, 5% CO2 농도 및 95% 상대습도에서 배양하였다.
인간 유도된 다능성 줄기 세포(hiPSC) 배양물
엔젤만 증후군으로 진단된 환자로부터 인간 전혈 샘플을 수득하였다. 1차 말초혈 단핵 세포(PMCS)의 후속 배양물을 적혈구모세포를 농축시켰다. 시토튠-iPS 센다이 리프로그래밍 키트(CytoTune-iPS Sendai Reprogramming Kit, 터모 피셔 사이언티픽)로 적혈구모세포를 리프로그래밍함으로써 환자-특이적 iPS 세포주를 생성하였다. 유도된 iPS 세포주는 매일 배지를 교체하면서 mTESR1(스템셀 테크놀로지스(STEMCELL Technologies)) 중의 hESC-적격 매트리겔(Matrigel, 코닝(Corning))을 사용하여 피더-비함유 조건하에 유지시켰다. 밀집상태(confluence)에 도달시, 콜로니들을 젠틀 세포 해리 시약(Gentle Cell Dissociation Reagent, 스템셀 테크놀로지스)을 사용하여 50 내지 200 ㎛ 크기의 세포 군집으로 해리시키고, 10 μM Y-27632(칼바이오켐(Calbiochem))의 존재하에 1:10 내지 1:20의 비로 계대배양하였다.
뉴런 전구 세포(NPC)로의 분화
뉴런 분화 유도시 iPSC-유래 세포들은, 1x B27(깁코, 인비트로겐), 1x N2(깁코, 인비트로겐), 0.1 mM 베타-머캅토에탄올(깁코, 인비트로겐) 및 나타낸 보충제로 보충된, 동일 부피의 DMEM:F12 글루타맥스 배지 및 신경세포배양용 배지(깁코, 인비트로겐)로 이루어진 기본 배지중에서 유지시켰다.
신경 전구 세포(NPC)는 hiPSC로부터 이중 SMAD 억제에 의해서 및 약간의 변경하에 공개된 절차에 따라서[Chambers et al. 2009 Nat Biotechnol. Vol. 3 pp.275-80, Boissart et al., 2013 Transl Psychiatry. 3:e294] 유도하였다. HiPSC를 어큐타제(Accutase, 이노베이티브 셀 테크놀로지스 인코포레이티드(Innovative Cell Technologies Inc.))로 단일 세포 현탁액으로 해리시키고, 10 μM Y-27632(칼바이오켐), 5 ng/ml FGF(페프로테크(Peprotech)), 10 μM SB-431542(칼바이오켐) 및 100 nM LDN(칼바이오켐)으로 추가 보충된 기본 배지에 재현탁시켰다. 단일 세포 현탁액을 어그리웰(AggreWell)800 플레이트(스템셀 테크놀로지스)로 옮겨 8000개 세포로 이루어진 응집체들의 생성을 가능하게 하였다. 5 일후에, 신경 응집체들을, 폴리-L-오르니틴(시그마) 및 라민(로슈)으로 코팅된 플레이트 위로 옮기고 FGF로 보충된 기본 배지중에서 지속적인 이중 SMAD 억제(SB-431542 및 LDN) 하에 신경 로제트(rosette)를 생성시켰다. 신경 로제트를 스템디프(STEMdiff)™ 신경 로제트 선별 시약(Neural Rosette Selection Reagent)(스템셀 테크놀로지스)을 사용하여 선택적으로 단리하고, 폴리-L-오르니틴 및 라민521(바이오라미나(BioLamina))로 코팅된 접시위에 재플레이팅하고, 10 ng/ml FGF(페프로테크), 10 ng/ml EGF(RnD) 및 20 ng/ml BDNF(페프로테크)로 보충된 기본 배지중에서 증식시켰다. 밀집상태에 도달하면, 세포를 0.05% 트립신(Trypsin)/EDTA(깁코, 인비트로겐)로 효소적으로 해리시키고 계대배양하였다. FGF, EGF 및 BDNF로 보충된 기본 배지중에서의 지속적인 계대배양에 의해 10 내지 20 계대 내에 안정한 신경 전구 세포주(NPC주)가 생성된다. 안정한 신경 전구세포주는 자기-재생되는 그의 능력에 의해서 및 발달 단계-특이적 마커 Sox2 및 네스틴(Nestin)의 발현에 의해 정의된다. 특정 자극시, NPC는 뉴런(MAP2+, Tau+, HuC/D+) 및 성상교세포(GFAP+) 자손세포로 분화된다[Dunkley et al., 2015 Proteomics Clin Appl. Vol. 7-8 pp.684-94].
NPC 배양
NPC 배양을 위한 조건은 이전에 기술되었으며 약간의 변경하에 이용하였다[Boissart et al., 2013 Transl Psychiatry. 3:e294]. 간략하게, 세포를 라미닌521(바이오라미나)로 코팅된 접시에서 유지시키고 기본 배지[1x B27(깁코, 인비트로겐), 1x N2(깁코, 인비트로겐), 0.1 mM 베타-머캅토에탄올(깁코, 인비트로겐)로 보충된, 동일 부피의 DMEM:F12 글루타맥스 배지 및 신경세포배양용 배지(깁코, 인비트로겐)로 이루어짐]중에서 배양하고 10 ng/ml FGF(페프로테크), 10 ng/ml EGF(RnD), 및 20 ng/ml BDNF(페프로테크)로 보충하였다.
뉴런 세포 배양물로의 분화
NPC의 뉴런 분화를 유도하기 위해, 세포를 0.05% 트립신/EDTA(깁코, 인비트로겐)를 사용하여 단일 세포 현탁액으로 해리시키고 라미닌521(바이오라미나) 코팅된 접시위에 12,000 세포/cm2의 밀도로 접종하고, 200 ng/ml Shh(페프로테크), 100 ng/ml FGF8(페프로테크), 및 100 μM 아스콜브산 포스페이트(시그마)로 보충된 기본 배지중에서 7 일의 기간동안 유지시켰다. 이어서, 세포를 20 ng/ml BDNF(페프로테크), 10 ng/ml GDNF(페프로테크), 0.5 mM cAMP(바이오로그 라이프 사이언스(BIOLOG Life Science)), 및 100 μM 아스콜브산 포스페이트(시그마)로 보충된 기본 배지중에 45000 세포/cm2의 밀도로 재플레이팅하고 21 일의 기간동안 분화시켰다. 분화 제 21 일에, 분화된 뉴런 배양물을 스크리닝-양립가능한 플레이트 포맷위에 재플레이팅하였다. 재플레이팅은 배양물을 어큐타제(이노베이티브 셀 테크놀로지스 인코포레이티드)로 단일 세포 현탁액으로 해리시킴으로써 수행하였다. 최종 올리고뉴클레오티드 스크리닝 분석을 위해 세포를 10 μM Y-27632(세포-투과성, 가역성, 칼바이오켐의 Rho 키나제의 억제제)의 존재하에서 200,000 세포/cm2의 밀도로 384 웰 미세적정 플레이트내에 접종하였다. 뉴런 배양물을 20 ng/ml BDNF(페프로테크), 10 ng/ml GDNF(페프로테크), 0.5 mM cAMP(바이오로그 라이프 사이언스(BIOLOG Life Science)) 및 100 μM 아스콜브산 포스페이트(시그마)로 보충된 기본 배지중에서 7 일동안 더 추가로 분화시켰다. 분화용 배지는 일주일에 2회 교체하였다. 35 일의 총 분화 기간 후에, 뉴런 세포 배양물을 올리고뉴클레오티드 처리를 위해 준비하였다.
인간 뉴런 세포 배양물에서 올리고뉴클레오티드 스크리닝 - 284 웰 시스템
스크리닝을 위해, 올리고뉴클레오티드 저장액을 나타낸 농도까지 물로 384 웰 미세적정 플레이트(화합물 플레이트) 내로 미리 희석하였다. 플레이트 레이아웃은 처리 주형의 역할을 하였다. 각 웰로부터 2 ㎕의 올리고뉴클레오티드 희석물을 화합물 플레이트로부터 각각의 배양 플레이트로 옮겼다. 모든 액체 취급은 반자동 실험실 로봇 시스템(베크만쿨터(Beckmancoulter))을 이용하여 층류에서 멸균 조건하에서 수행하였다. 뉴런 세포 배양물은 배지 교환없이 5 일동안 올리고뉴클레오티드와 함께 배양하였다. 이어서, 뉴런 배양물을 세포용해시키고 실시간 사용가능한 세포 용해 및 RNA 바이러스 마스터 키트(RealTime ready Cell lysis and RNA Virus Master kit)(로슈)를 사용하여 qPCR 분석을 위해 가공하였다. 액체 취급은 반-자동 실험실 로봇 시스템(베크만쿨터)을 이용하여 수행하였다. 샘플들은 라이트사이클러(Lightcycler)480 실시간 PCR 시스템(로슈)으로 분석하였다.
올리고뉴클레오티드의 활성은 하기의 프라이머 및 프로브들을 사용하여 UBE3A의 전사체 풍부도를 qPCR 모니터함으로써 평가하였다:
UBE3a-센스: 정방향 프라이머: ATATGTGGAAGCCGGAATCT (서열번호 837),
역방향 프라이머: TCCCAGAACTCCCTAATCAGAA (서열번호 838),
염료 FAM으로 표지된 내부 프로브: ATGACGGTGGCTATACCAGG (서열번호 839).
RT-qPCR을 표준화를 위한 항존 유전자로서 PPIA(펩티딜프로필 이소머라제 A)로 다중화시켰다. 염료 VIC로 표지된 PPIA 프라이머 및 프로브는 터모 피셔 사이언티픽으로부터 구입하였다(분석 ID Hs99999904_m1). 각각의 플레이트는 음성 대조군으로서 비-표적화 올리고뉴클레오티드(모조물)(TTGaataagtggaTGT (서열번호 846)) 및 기준 올리고뉴클레오티드 CMP 번호 41_1을 포함하여, UBE3A mRNA의 상향조절을 야기하였다.
올리고뉴클레오티드의 선택성은, 염색체 15상의 SNORD109B의 상류에 위치한 SNORD 115 전사체에 대한 상대 스크리닝에 의해 확인하였다. SNORD115의 발현은 하기 프라이머 및 프로브를 사용하여 qPCR에 의해 모니터하였다:
정방향 프라이머: GGGTCAATGATGAGAACCTTAT (서열번호 840),
역방향 프라이머: GGGCCTCAGCGTAATCCTATT (서열번호 841),
염료 FAM으로 표지된 내부 프로브: TTCTGAAGAGAGGTGATGACTTAAAA (서열번호 842).
올리고뉴클레오티드 처리시 RT-qPCR을 PPIA(터모 피셔 사이언티픽)로 다중화시켰다.
SNORD109B 하류의 SNHG14 전사체(UBE3A 억제유전자로도 지칭됨)의 감소는 하기 프라이머 및 프로브를 사용하여 RT-qPCR로 측정하였다:
정방향 프라이머: atccgaggcatgaatctcaC (서열번호 843),
역방향 프라이머: caggccaaaacccttgataa (서열번호 844),
염료 FAM으로 표지된 내부 프로브: ttgctgagcatttttgcatc (서열번호 845)
RT-qPCR을 PPIA(터모 피셔 사이언티픽)로 다중화시켰다.
데이터는 모든 플레이트들 전체에 걸쳐 모조물에 대한 평균 %발현율로 나타내고, 플레이트 대 플레이트 변화를 고려하기 위해 기준 올리고뉴클레오티드로 표준화시킨다.
인간 뉴런 세포 배양물에서 올리고뉴클레오티드 스크리닝 - 96 웰 시스템
스크리닝을 위해, 올리고뉴클레오티드 저장액을 나타낸 농도까지 물로 96 웰 미세적정 플레이트(화합물 플레이트) 내로 미리 희석하였다. 플레이트 레이아웃은 처리 주형의 역할을 하였다. 각 웰로부터 2 ㎕의 올리고뉴클레오티드 희석물을 화합물 플레이트로부터 각각의 배양 플레이트로 옮겼다. 모든 액체 취급은 반자동 실험실 로봇 시스템(베크만쿨터)을 이용하여 층류에서 멸균 조건하에서 수행하였다. 뉴런 세포 배양물은 배지 교환없이 5 일동안 올리고뉴클레오티드와 함께 배양하였다. 이어서, 뉴런 배양물을 세포용해시키고, RNA 정제 키트 퓨어 링크 프로 96(Pure Link Pro96)(12173011A)(라이프 테크놀로지스)를 사용하여 RNA를 정제하였다. 액체 취급은 반자동 실험실 로봇 시스템(베크만쿨터)을 이용하여 수행하였다. Ube3a 및 Ube3a-ATS의 qPCR 분석은 ViiA™ 7 실시간 PCR 시스템(터모 피셔 사이언티픽) 상에서 콴타의 qScript™ XLT 1-스텝 RT-qPCR 터프믹스 로우 록스(95134-50)를 사용하여 수행하였다.
하기 프라이머 및 프로브를 사용하였다:
qPCR UBE3a-센스:
정방향 프라이머: ATATGTGGAAGCCGGAATCT (서열번호 697),
역방향 프라이머: TCCCAGAACTCCCTAATCAGAA (서열번호 698),
염료 FAM으로 표지된 내부 프로브: ATGACGGTGGCTATACCAGG (서열번호 699).
SNORD109B 하류의 qPCR SNHG14 전사체(UE3A 억제유전자로도 지칭됨): 터모피셔에서 상업적으로 시판하는 프라이머 및 프로브 세트: Hs01372957_m1. 이들 프라이머는 진뱅크(Genbank) 전사체 AF400500.1의 87 bp 엑손-엑손에 걸친 서열을 증폭시킨다.
QPCR GAPDH 전사체:
터모피셔에서 상업적으로 시판하는 프라이머 및 프로브 세트: 유전자 기호: 하기의 분석 세부사항 하에: RefSeq: NM_002046.3, 프로브 엑손 위치: 3, 앰플리콘 크기: 122 bp. 상응하는 태크맨 분석 ID: Hs99999905_m1.
Ube3a 및 Ube3a-ATS 둘 다에 대한 RT-qPCR을 표준화를 위한 항존 유전자로서 GAPDH로 다중화시켰다. 각각의 플레이트는 음성 대조군으로서 비-표적화 올리고뉴클레오티드(모조물)(TTGaataagtggaTGT (서열번호 846)) 및 기준 올리고뉴클레오티드 CMP 번호 21_1을 포함하여, UBE3A mRNA의 상향조절을 야기하였다. 또한, Ub3a 또는 SNORD109B 하류의 qPCR SNHG14 전사체(UE3A 억제유전자로도 지칭됨)를 표적화하지 않는 올리고들의 패널을 분석 잡음 및 위양성을 검출할 위험성을 모니터링하기 위해 포함시켰다. 이들은 플레이트 상에 무작위로 분포되었다.
대조군 올리고뉴클레오티드:
Figure 112020127052610-pat00122
Figure 112020127052610-pat00123
실시예 1 - 마우스 1차 뉴런 세포 배양물에서의 올리고뉴클레오티드 활성
UBE3A 전구체-mRNA에 대해 안티센스인 SNHG14 긴 비-암호화 RNA 부분(서열번호 1의 위치 55319 내지 141053)을 표적화하는 올리고뉴클레오티드를, 상기 "재료 및 방법" 부분에서 기술된 바와 같이 수득된 마우스 1차 피질 뉴런 세포 배양물에서 UBE3A 발현을 방해하는 SNHG14 긴 비-암호화 RNA 전사체(데이터 표에서 UBE3A 억제유전자 또는 UBE3A-SUP로도 지칭됨)를 감소시키는 그의 능력 및 UBE3A mRNA 재발현을 유도하는 그의 능력에 대해 검사하였다. 올리고뉴클레오티드 농도는 5 μM이었다.
올리고뉴클레오티드는 "재료 및 방법" 부분에서 기술된 마우스 피질 뉴런 세포 배양물에서의 스크리닝을 위한 프로토콜에 따라 스크리닝하였다. 결과는 표 4에 나타내었다.
[표 4]
1차 마우스 뉴런 세포 배양물에서의 올리고뉴클레오티드 활성
Figure 112020127052610-pat00124
Figure 112020127052610-pat00125
실시예 2 - 인간 뉴런 세포 배양물에서의 올리고뉴클레오티드 활성
염색체 15 상의 위치 25278410 내지 25419462에 상응하는 SNORD109B 하류 영역(서열번호 1)의 인간 SNHG14를 표적화하는 올리고뉴클레오티드를 환자 유래 인간 뉴런 세포 배양물 중에서 검사하였다("재료 및 방법" 부분의 프로토콜 참조). SNORD115의 발현에 영향을 미치지 않으면서, SNORD109B 하류 영역의 SNHG14 전사체(데이터 표에서 UBE3A 억제유전자 또는 UBE3A-SUP로도 지칭됨)를 감소시키는 올리고뉴클레오티드 능력을 분석하였다. 또한, UBE3A mRNA 재발현을 유도하는 능력을 분석하였다.
올리고뉴클레오티드는 상기 "재료 및 방법" 부분에서 기술된 인간 뉴런 세포 배양물에서 올리고뉴클레오티드를 스크리닝하기 위한 프로토콜에 따라 스크리닝하였다.
결과는 표 5에 나타내었다. UBE3A mRNA의 발현은 모든 화합물들에 대해 측정한 반면, UBE3A 억제유전자의 녹다운 및 SNORD115 수준의 유지는 모든 화합물에 대해 분석하지는 않았다.
[표 5]
환자 유래 인간 뉴런 세포 배양물에서의 올리고뉴클레오티드 활성
Figure 112020127052610-pat00126
Figure 112020127052610-pat00127
Figure 112020127052610-pat00128
Figure 112020127052610-pat00129
Figure 112020127052610-pat00130
Figure 112020127052610-pat00131
검사한 187개 화합물들 중에서 약 90%가 5 μM 농도에서 모조물 올리고뉴클레오티드와 비교시 UBE3A의 재발현을 나타내었다. UBE3A의 재발현을 유도할 수 있는 올리고뉴클레오티드의 수는 UBE3A 암호화 영역에 상보적인 영역(중복 영역)에서보다 서열번호 1의 위치 1 내지 55318 사이의 영역(비-중복 영역)에서 더 높다. 도 2는 염색체 15 상의 그 위치에 따른 올리고뉴클레오티드의 분포 대 모조물 올리고뉴클레오티드에 대한 UBE3A mRNA 발현을 도표화한 것이다.
SNORD115가 검사된 올리고뉴클레오티드의 경우, 1 및 5 μM에서 모조물과 비교시 의미있는 하향조절은 없다.
실시예 3 - SNORD109B의 하류 및 UBE3A 전구체-mRNA에 대해 안티센스인 영역의 상류의 영역에서 SNHG14 전사체를 표적화하는 올리고뉴클레오티드의 활성
서열번호 1의 위치 4806 내지 54939를 표적화하는 올리고뉴클레오티드를 환자 유래 인간 뉴런 세포 배양물에서 검사하였다("재료 및 방법" 부분의 프로토콜 참조). SNORD109B의 하류 영역의 SNHG14 전사체(데이터 표에서 UBE3A 억제유전자 또는 UBE3A-SUP로도 지칭됨)를 감소시키는 올리고뉴클레오티드의 능력을 분석하였다. 또한, UBE3A mRNA 재발현을 유도하는 능력을 분석하였다.
올리고뉴클레오티드는 "재료 및 방법" - "인간 뉴런 세포 배양물에서 올리고뉴클레오티드의 스크리닝 - 96 웰 시스템" 부분에서 기술된 인간 뉴런 세포 배양물에서 올리고뉴클레오티드를 스크리닝하기 위한 프로토콜에 따라 스크리닝하였다.
결과는 표 6에 나타내었다.
[표 6]
환자 유래 인간 뉴런 세포 배양물에서의 올리고뉴클레오티드 활성
Figure 112020127052610-pat00132
Figure 112020127052610-pat00133
Figure 112020127052610-pat00134
Figure 112020127052610-pat00135
Figure 112020127052610-pat00136
Figure 112020127052610-pat00137
Figure 112020127052610-pat00138
Figure 112020127052610-pat00139
Figure 112020127052610-pat00140
Figure 112020127052610-pat00141
Figure 112020127052610-pat00142
Figure 112020127052610-pat00143
Figure 112020127052610-pat00144
Figure 112020127052610-pat00145
Figure 112020127052610-pat00146
Figure 112020127052610-pat00147
Figure 112020127052610-pat00148
실시예 4 - UBE3A 전구체-mRNA에 대해 안티센스인 영역의 SNHG14 전사체를 표적화하는 올리고뉴클레오티드의 활성
서열번호 1의 위치 55337 내지 136214를 표적화하는 올리고뉴클레오티드를 환자 유래 인간 뉴런 세포 배양물에서 검사하였다("재료 및 방법" 부분의 프로토콜 참조). SNORD109B의 하류 영역의 SNHG14 전사체(데이터 표에서 UBE3A 억제유전자 또는 UBE3A-SUP로도 지칭됨)를 감소시키는 올리고뉴클레오티드의 능력을 분석하였다. 또한, UBE3A mRNA 재발현을 유도하는 능력을 분석하였다.
올리고뉴클레오티드는 "재료 및 방법" - "인간 뉴런 세포 배양물에서 올리고뉴클레오티드의 스크리닝 - 96 웰 시스템" 부분에서 기술된 인간 뉴런 세포 배양물에서 올리고뉴클레오티드를 스크리닝하기 위한 프로토콜에 따라 스크리닝하였다.
결과는 표 7에 나타내었다.
[표 7]
환자 유래 인간 뉴런 세포 배양물에서의 올리고뉴클레오티드 활성
Figure 112020127052610-pat00149
Figure 112020127052610-pat00150
Figure 112020127052610-pat00151
Figure 112020127052610-pat00152
Figure 112020127052610-pat00153
Figure 112020127052610-pat00154
Figure 112020127052610-pat00155
실시예 5 - SNORD109B의 하류 및 UBE3A 전구체-mRNA에 대해 안티센스인 영역 상류의 영역의 SNHG14 전사체를 표적화하는 올리고뉴클레오티드의 활성
서열번호 1의 위치 5224 내지 51257을 표적화하는 올리고뉴클레오티드를 환자 유래 인간 뉴런 세포 배양물에서 검사하였다("재료 및 방법" 부분의 프로토콜 참조). SNORD109B의 하류 영역의 SNHG14 전사체(데이터 표에서 UBE3A 억제유전자 또는 UBE3A-SUP로도 지칭됨)를 감소시키는 올리고뉴클레오티드의 능력을 분석하였다. 또한, UBE3A mRNA 재발현을 유도하는 능력을 분석하였다.
올리고뉴클레오티드는, 하기의 변경하에 "재료 및 방법" "인간 뉴런 세포 배양물에서 올리고뉴클레오티드의 스크리닝 - 96 웰 시스템" 부분에서 기술된 인간 뉴런 세포 배양물에서 올리고뉴클레오티드를 스크리닝하기 위한 프로토콜에 따라 스크리닝하였다:
UBE3a-센스 프라이머
터모피셔에서 상업적으로 시판하는 프라이머 및 프로브를 사용: refseq ID NM_000462.3의 위치 838의 94 bp 서열을 증폭시키는 Hs00166580_m1.
각각의 플레이트는 PBS 대조군(비-표적화 올리고뉴클레오티드 대신) 및 양성 대조군 올리고뉴클레오티드 CMP 번호 271_1을 포함하여, UBE3A mRNA의 상향조절을 야기하였다. 추가의 대조군 올리고뉴클레오티드는 포함되지 않았다.
데이터는 모든 플레이트들 전체에 걸쳐 PBS 대조군에 대한 평균 %발현율로 나타내고, 효능 수준에서 플레이트 대 플레이트 변화를 조정하기 위해 양성 대조군 올리고뉴클레오티드로 표준화시켰다. 결과는 표 8에 나타내었다.
[표 8]
환자 유래 인간 뉴런 세포 배양물에서의 올리고뉴클레오티드 활성
Figure 112020127052610-pat00156
Figure 112020127052610-pat00157
Figure 112020127052610-pat00158
Figure 112020127052610-pat00159
Figure 112020127052610-pat00160
Figure 112020127052610-pat00161
Figure 112020127052610-pat00162
Figure 112020127052610-pat00163
Figure 112020127052610-pat00164
Figure 112020127052610-pat00165
Figure 112020127052610-pat00166
Figure 112020127052610-pat00167
Figure 112020127052610-pat00168
Figure 112020127052610-pat00169
Figure 112020127052610-pat00170
Figure 112020127052610-pat00171
Figure 112020127052610-pat00172
Figure 112020127052610-pat00173
Figure 112020127052610-pat00174
Figure 112020127052610-pat00175
Figure 112020127052610-pat00176
실시예 6 - 엑손-엑손에 걸친 올리고뉴클레오티드의 활성
SNHG14-023(ENST00000554726)의 엑손-엑손 접합부 전체에 걸쳐 상보적이도록 설계된 올리고뉴클레오티드를, SNORD109B 하류 영역의 SNHG14 전사체(데이터 표에서 UBE3A 억제유전자 또는 UBE3A-SUP로도 지칭됨)를 감소시키는 그의 능력에 대해 검사하였다. 또한, UBE3A mRNA 재발현을 유도하는 능력을 분석하였다. 상기 올리고뉴클레오티드는 주로 엑손2 및 엑손3에 걸쳐있다(즉, 엑손2의 영역 및 엑손 3의 영역에 상보적이다).
올리고뉴클레오티드를 실시예 5 부분에서 기술된 인간 뉴런 세포 배양물에서 올리고뉴클레오티드를 스크리닝하기 위한 프로토콜에 따라 스크리닝하였다.
결과는 표 9에 나타내었다.
[표 9]
환자 유래 인간 뉴런 세포 배양물에서의 올리고뉴클레오티드 활성
Figure 112020127052610-pat00177
실시예 7 - 선별된 올리고뉴클레오티드들의 시험관내 효능 및 효력 검사
상기 실시예 2 내지 5에서의 스크리닝에 기반하여, 52개 올리고뉴클레오티드를 효력 및 효능 검사를 위해 선별하였다.
올리고뉴클레오티드는, 하기의 변경하에 재료 및 방법 부분 "인간 뉴런 세포 배양물에서 올리고뉴클레오티드의 스크리닝 - 96 웰 시스템"에서 기술된 바와 같이 인간 AS 환자 유래 세포에서 스크리닝하였다:
UBE3a-센스 프라이머의 경우 터모피셔에서 상업적으로 시판하는 프라이머 및 프로브: refseq ID NM_000462.3의 위치 838의 94 bp 서열을 증폭시키는 Hs00166580_m1을 사용하였다.
각각의 플레이트는 PBS 대조군(비-표적화 올리고뉴클레오티드 대신)을 포함하고, 이전의 스크리닝에서 확인된 양성 대조군 올리고뉴클레오티드 CMP 번호 186_1 및 39_1이 포함되었다. 재료 및 방법 부분에서 기술된 추가의 대조군 올리고뉴클레오티드는 포함되지 않았다. 올리고뉴클레오티드 검사 농도는 10 포인트 반-로그 희석법을 이용하여 31.6 μM 내지 1 nM이었다. 모든 올리고뉴클레오티드는 상이한 5번의 일주일에 5가지 독립적인 실험에서 검사하였다. 데이터 QC 과정에서, 일부 플레이트는, 이들이 분명한 이상치인 경우, 예를 들면, PCR 산물이 검출되지 않은 경우 분석에서 배제시켰다. 상기 걸러내기 후에, 각각의 보고된 값들 뒤에는 최소 3개의 독립적인 실험들이 남는다.
4개 파라미터 S자형 용량-반응 모델을 이용하여 곡선 적합화후 EC50(UBE3A mRNA 재발현) 및 IC50(데이터 표에서 UBE3A 억제유전자 또는 UBE3A-SUP로도 지칭된, SNORD109B 하류 영역의 SNHG14 전사체의 감소)을 측정하였다. 적합화는 IDBS(XLfit)에 의한 바이오북(Biobook) 소프트웨어 내부에서 이용가능한 적합화 엔진을 이용하여 실행하였다. 곡선-적합화로부터 수득가능한 UBE3A의 최대 상향조절(UBE3A Max Up) 및 수득가능한 UBE3A-SUP의 최대 녹다운(UBE3A-SUP max Kd)을 측정하였다. 둘 다 대조군(PBS 처리된 세포)의 %로서 나타내었다. 결과는 표 10에 나타내었으며, 값들은 각 생물학적 복제물의 기하평균으로 보고되었다.
[표 10]
올리고뉴클레오티드 EC50 및 IC 50 값 및 최대 UBE3A 상향조절 및 UBE3A 억제유전자 녹다운
Figure 112020127052610-pat00178
Figure 112020127052610-pat00179
Figure 112020127052610-pat00180
SEQUENCE LISTING <110> F. Hoffmann-la Roche AG <120> OLIGONUCLEOTIDES FOR INDUCING PATERNAL UBE3A EXPRESSION <130> P32756-EP <140> PCT/EP2016/077383 <141> 2016-11-11 <150> EP15194367.7 <151> 2015-11-12 <150> EP16189502.4 <151> 2016-09-19 <160> 846 <170> PatentIn version 3.5 <210> 1 <211> 141053 <212> DNA <213> Homo sapiens <400> 1 agatgtgcgg ccctccaata ggacaaataa gactctcaga gcctggctct atttggggat 60 ccctcagtga caacatagta cccctgtgag cgtgcctttt ctatctcttc gaagagggca 120 gtggcatcct gtcttatgag tcagtgtgca ctttagtgtg cctagtgacc caagacttgc 180 tttaattgta gatagatact tacatatagg aaatatttct taagtaacaa atgaaaaact 240 ttagaagatt gaattaaggg tcaagcaact gtgatatgtc tgaaaatctc attagtgttg 300 tgctgaaaga aggaaatatg gcatgcctct attaaataat gacagtggaa ccaagtttat 360 tgctttgtta tttttactgt ggagtatttt ctaagattat ttttgctttt tttttctttc 420 atgttttgct gagatagaag gcctggaatc tgatcctcca cttcagagaa caggggtgag 480 tagctaagcc attatctttt gaaattcata tgtcatgtgc tctttgctag gtctttaggt 540 cgttttgtac atcttttcag aagcttattg gaggacattt tcatgatatg tccttttcct 600 cattgagacc ctcaccatgt cacctacact attgaatcct tatcatttct cttttaattt 660 taactctctt ttgcttttat ggaaaaatgt agaatttaag agaatttttg gcaatttcat 720 attggatcaa aatgtattgt agtgaaatcc aggtgtgcca aaatattaac agattttccc 780 catctgttta attattgggg tttcagaata gagactccat ggttcataat atctttgtgg 840 tcatactaca ttatatttct gcttctaatt taattattaa atattgactt gaattagtct 900 tttcctcatt gttgcaacaa ggtaagttat ataggaaatt ttcttctctt gatggcatgt 960 ctgagataat catagatata agacacctgg ctggtttcta gaatgcatgt aatttttatt 1020 tcttgatctg tgtgttgagt acttgctgtg attgcatcat gcaaatacat tgagctttac 1080 aattttagtg tatgcacttt tctacatgta tattattctt cgatagaaag taaaaaaaac 1140 ttatcgaact agtcaaaata ttggttaata cataaaaaaa gtctcaagta gattgtgtat 1200 tacatggtgc ttgttgattg atgccctcat aatagatcaa gtgggttctc tctttagcac 1260 agggcttttt agcaaatcat gtcatgagta gttactcaag tatttttatt ttaacacatt 1320 tatatttttt ctatgtatat tcttaaattc tcttatactt ttttctctgt tataaaaaca 1380 tgctgaacaa tctcaagtct taaggattgc agtattgtcc ccacatattc atgtattttg 1440 gtactcaatt ctttatactt tctttgacag atcacttgaa ctggcacatg tctcttgttt 1500 tgcagagagg gaattaatgt gataccttca tgcttttcta ttctatgtgc tacataattg 1560 aatatacaag caaatatagt tgttaagatt tagtgtgatt atttctacac cacatgcaaa 1620 gaagtttctc atagatctta atagaggccc acatgcattg tacagtttag aatttgggga 1680 aatattgatg aagttgggta aagtataaag ccaaaagtca gaacagtgaa ctccttgctt 1740 aaggatttcc ttggagatta cttagtcaat acacaactga taaatttaag tgcttttcac 1800 cttttgagtt ctcgacatac taaagctaaa atgtgtttca acttttaatc ctgcttccct 1860 gattttccct tttttagtct gagatcaaag agtttcagcc ataaattact gccaagagta 1920 atcacttcat tttaagaaag cttaacaata tagaagaata taaaattatt tatgacagat 1980 gtatttttaa ccttttcccc atgctttcca gaggaaatat gtttaatcat ctgccctata 2040 ttagggaaaa actttctatg ctaatacaag tatctatcaa tccatttatc tttctatata 2100 agatgtattg atcataacca attaacttta ctgtaaatga gctttagatt tgacattttg 2160 gtagtaatat atgttgtaca atctcctgag gtcctatagg tcttgaggtc tctatgtcaa 2220 aaactataga tgtgccagtg tcctcagtga atgtgaagga caccacattt tccttagcca 2280 tttcttgttt tcagaataat ggttatcaac attttgctac tgcaagatac catacattta 2340 taatcggaat atgccagttt ttatgcactc atgcctctgt ttctgtagag cattcccaga 2400 atgagtaatg cttgaaaatt aggtccatgt gatttcttta atgagttata gtcaaatcat 2460 gaaatattca ggttaccatt atttcagtaa tgtattagaa tgtcaaggta aagttatcta 2520 cattgtatat atacacacaa catagatata atttatacaa catctatatt tatacaacag 2580 atatatattt atgtatatat ttatacaaca taaaatatat tttattattt aaacataaaa 2640 tatattttat tatttaatat agattcttaa gtgataaata tgtttaatat tattaaaata 2700 ggttaaaata ggttatagtt agtacagtga aaattggcag cccttttaca aaacatatgc 2760 cataactata gcatttatca ctgacagtca taccaggata gtcttttatt tccaatcact 2820 taaatattcc taattgcaaa agaaatttga agactaaaat tcagaagttt tgaaagagcc 2880 attgcctggg taaactatac aggtttcagt tttatttata ataattatga ggccaggcgc 2940 agtggctcac acctgtaatc ccaacacttt gggaggccga ggcgggtgga tcacgaggtc 3000 aggagatcga gaccatcctg gctaacacgg tgaaacccca tctctactaa aaatacaaaa 3060 aattagccgg gcgtggtggc gggcgcctgt agtcccagct actcgggagg ctgaggcagg 3120 agaatggcgt gaacctggta ggcggagctt gcagtgagcc gagatcgcgc cactgccctc 3180 cagcctggga gacagtgcga gactccgtct caaaaaaaaa aattatgtat atatttataa 3240 attaatactt aataaattaa taacttgtga taggcaatgc aaagatgaca gtaaaaggac 3300 aaaattgatt agattgataa agtcctgtta acatgaagaa attgaccagg ataccatcca 3360 cactataaag ttagagaaat ttatcaggac aattccctaa aatactcttc tcaattttaa 3420 cattgtaaca ggaattttta aaattttggt attatgtgtg tttccttcca gataatttga 3480 acagattcat atttggtatt tttaaaagcc atatctttgt ccttagtgct ggcaatgtat 3540 tcttgagaat gaacaaataa gagatacgta aaagcataag agaaggtatc aggttgaagt 3600 agtcaatcag ttatacagaa cacaaagaat tttatcttgt ataatgttta tatagcttta 3660 tagaagtgtg ctgaaagggc tataaaacat ggacattatt atctcattga aaggtccaat 3720 acgtactgaa atacatgctt ttattttgaa ccaaccaccc tataaacgtt gtatggctta 3780 tttagatgag agcccaggtt gtgtgtgtct gtgtgtgtgt gtgtgtgtgt gtgtgtgtgt 3840 gtgtgtgtgt gtgtacctga cagggaagca agaacatcga gttgccaatg cactctgtct 3900 atggttagaa tcatgctgaa aacatggctc ccccagttct ggaatgagcc cacagatcaa 3960 gcattcccca aagacatagc aggctcaaat ccctgtgtac acaatatttt atgattatct 4020 tatgtcagta ctttcaaagt atacagtttg tgtgaagaca aatccaatgt catttttctt 4080 ggctagccta tatgtgtggt aaatccatta tttacttact tgcttcctga aaattacaat 4140 tagattaaca aactgcagca aagtgggcat gatgagatag agattgaagt gtaagcttat 4200 gttaatgatg cccttggttt ggataaacac atctaagaga aaaatggaaa aacacacatg 4260 gcagggaagc cttgatagag ccaaaatata ggattgtatg tagtaatgca atccatagat 4320 gagcatttgg cagtaatatt atttttcaga tatggataaa aattgcttag gagagtaaag 4380 agagacaaag ttgaaagcag gtttatagta ggtgttgttt tagtgttgat ccctttttgc 4440 tccaataatc aaagtgataa atattgaaaa ttgattcatg cagcattact tactccattc 4500 taatttttat atatgtcaaa agtgccatct cccaaactgt gctatcccct tcaggagaag 4560 agactctgct gaagtttata aggttgacat attgccagct tcaataatgt aaagatgaag 4620 tgtatactga attcttaatg caaataacaa ctctattgga aagtaaccca gttatagaag 4680 tgctaatttg tcaggagctg ccttaccaag atcatgatga gtacagttat ctcaggattc 4740 tgaaagattg ttttccgatt tcaactagtc tagctgaatg ttccttgata gaaagagagg 4800 acttttagaa ttggttcaat atgatgacct cctgaattat ctcacatagc ccgtttgtac 4860 atgcctttct tttctctcag aaaatggcac tatcataata gctttcttac acagacttca 4920 ccttagggtt ttacattaag ggaggggtct ggtgtttcat ttattttgaa gtatttgttg 4980 ttgattgtgt acagtgcttg agtaaaaaat tgaatataga aacatctaga atattttttt 5040 aaaggatcag tgtttataaa gtgaattatt agtgtcaata atgttgggaa agttttaaga 5100 gaatatagga aacttgaaca ttacacaact acaatgggac caaattgtgg ggtctcatta 5160 tagttaatat ttatgtattt ttttccaatt gatttgtgtg ctttttttct gcatgttttt 5220 ggcagataga atggctataa caagtaacag catgtcaggt aataaaaata agcagagccc 5280 tattccttta aaaatcttca ctgatgggag ggccataaaa taagtcttaa tacatttaaa 5340 gaattaaatt catgtaaacc atgttaattt aattccacaa tgatattgaa ttagaaataa 5400 gaggaatatc tcttgaacat ctcctaaatg tttggaaatt taaattagca tttctgacct 5460 atttattggt taaaaaagat acaaagaaag gaaaattgaa aagtcttttg aactgaataa 5520 aaataaaaat atagaatcta aaactttatg ggatactgac aaaacaggat atagggaata 5580 atttatagca ctgaaatgcc tatattagaa aagaaaaaag gttttaaatc agtaaatttg 5640 tattttacct taagaaactt agaaaagaac aaattaaccc agacttaagt aaaataaagg 5700 cactaataaa gataagagca gaaatcaatg aaatataaaa caacaaaaca cagagaaaaa 5760 ttgagaaaat ttaaaaatag cctagtgaga agatattgat aaacttgtaa ccagaccaat 5820 ttaagaaaaa aagtcaaaac acaaatacca atatttgaaa atgtaggagg gcaaatcatt 5880 acagattcta tgaatactaa aatgataata aggaaaaatt atttaaaagg ggcatgtcag 5940 ccaggcatgg tggcttaccc ctgtaatccc agcactttgg caggccgagg tgggaggatt 6000 gctagagctc aggcattcga gaccagcctg ggcaacatgt tgaaaccttg tctacacaaa 6060 aagtacaaaa attagctggg tgtggtgttg cacacttgta gtcccagtca cttgggaggc 6120 tgaggcgaga ggatcacttg agcccaggag gttgaggctg cagtgagcca tgtttgtacc 6180 actgccctcc agcctgggtg acaaagtaag accctatgta aaaaaaaaaa aatgtatgcc 6240 aacatttttc aataacttaa atgaaatgga aaaattcctt gaaagacacg aactacaaaa 6300 actcagtgaa caagtaaata acctgaatag ccctgtatca agtaaattga atttgtagtt 6360 aaaagccttc caacagagaa aacttcaggt acctatagct tcatatgaaa tgaaaaaaaa 6420 aataccaatc ctctacaaga ttccagaaca tttaaaagaa gggaatattt cccaacttat 6480 tccatttgga cagcaatacc caggtaagaa aaagagacac agaaatttaa aaagaagaat 6540 atacattatt ccttaggaac ataaatgcaa agaaatctaa tcaaaatttt ggcaaatgaa 6600 atgtagaaat actttatgac caagtgagag ttacccaaag aatttaaggt tggttttata 6660 tgtaaagatc aaccaatata ggaaaatcac ttctggaaag tcagagtaag aaactccaaa 6720 aatctactcc tccataaaac caataacagc cttgatagaa atagttgaaa ttaattttcc 6780 aaaactttgg aaattaacca aaggcttaca aaattccaga gaacattaat tcaagaaaaa 6840 tggctgaatc agtaagaaca gccagctttg tggcatttta atatgacccc ttcccatgct 6900 tttctcccta gtgctgagat agtcttaaaa attagcagga tagcaaccac tggagaagaa 6960 aggtttggaa atttcccaaa aagttccatc cccatagaat tatcactatt tgacctctaa 7020 agcccaatct ataggattta tattcatttg gactgactca gagctcactc agtaaggaaa 7080 tctcaatttc aaggtattgg tcaaaaagaa tccatggcaa ttgttgacta tcacaactgc 7140 ctgaagtctt ggtaacagtt gggataaaca agaagctgat caaaaactga aaactaaaat 7200 cttgggaatg agatatctac aggatgcttc aaaaagcttt gatacattcc tgtttatcta 7260 gaaagctaca tgcaggctgg gtgcagtggc tcacacctgt aatcccagca ctttgggagg 7320 ccgaggcgtg cggatcatga ggtcaggagt ttgaggccag cctgaccaac atggtctcta 7380 ctaaaaacac aaaaattagc caggcgtggt ggcgtgcatc tgtaatccta gctactcagg 7440 aggctgagac aggagaatcg cttgaacccg ggaggcggag gttgcagtga gccaagattg 7500 tgccactgca ctccagcctg ggcgacagag caaggctctg tctcaaaaaa aaaaaaaaaa 7560 aaagccacat gcatgtaatt gtttacctct ggctttcctt ttatgctctg ggcaagctaa 7620 ggaagagttg tgaactacct aagtgctgaa tgggaaccat aacacacaca cacacacaca 7680 cacacacaca cacagcacct tagtaaaggg tgagaggcat gttagttaga agcattaaag 7740 gaaatctctt tctagtcatt atctgtgcac taacctaact gagcagagac ttcagtatcc 7800 acatactaca gggcatataa actttacaga attagtccag gaaaatcata tctaaaaaaa 7860 aaaaaaagca gtaacaaaaa taaactctgg gaaaggggag aatatgattt aaagagttgc 7920 cacattatac ataatatgtc tagtgttcaa caaaaaatta cgagacatgc aaagaaatag 7980 aaaaatatgg cacaaagagg ataagatgaa gtcagtgaaa ctatcctcga ggaagaccag 8040 atgttggtct tactagacac agacattgaa ccagctatta aaaatacgta cacagaacta 8100 agaaaaacat gtcaaaaggg ttaaagaaag gtataaaaat agtgtcttac caaatataga 8160 ctaccaataa agagatagaa attataagaa aagacaacat gaaaaaatat aaagcaaaaa 8220 aattagacaa ttgaaacaag agggcctcta ttcgcagatt tgagcaggca gaagaaagaa 8280 tcagtgaact tgaagatatg tcaactgaga ttatccagtc tgagcaacaa aggtgggaaa 8340 aaatgaagaa aactgagcaa caaagaactg tagaacagca tctctcatac caatggatac 8400 ataaactgga gccctagaag gatgaaaaaa ggagaaggaa agaaaacttc ccaaatttta 8460 agaaaaacat taatttatat acccgagatg accaataaaa tccaattaag ataatctcaa 8520 agagaccaac acctatacac atcatagtca gcgtgtcaaa agacaaacat aaggagagaa 8580 ttcttgaaga tagtaagaaa aaaattattc ataacataca caccatcctc aataagtctg 8640 acaattgact tctcactgta aaccatgcag gctaaaaagg caatgtacat aaccaaagtg 8700 atgaaataaa aaccttcaac caatcattct agatccaaca aaactattgt tcaaaaagaa 8760 gaaatgaaga cattcctaaa caaaatctca gagaaatgtt ctctataaga cttgtcctaa 8820 tagaaatgct aaaggaactc cttcggtctg aaatagaaag gcactggaga gtaaatcaaa 8880 tccacgagaa gaaataaaga gaaccagtat aagtaactac atgtgtaagt ttaaaacaaa 8940 gtataaattt attttgtttg taacatttgt cttttcctat ttgatttaaa atataatctc 9000 aattataaac ttgtgttgat ggtattatat aaagatgtaa ttttgggtta tagcaccaaa 9060 atggcagaat aggaattttc tgtaggtgtt tcccacataa gtatcaattt tgacaaccat 9120 ccatgggcaa gagtaccttg tgggagttca ggagttgaca gtaaaacttc agcacaccag 9180 aggagtaaag aaatctaaga atagattcat tggaaagggt ataaacagtt tcactttacc 9240 tgcatcacca acccccaaaa gtggcacagc tcagtaacaa gagcccatta tttcttccac 9300 agaggaaaag gagagtataa taagtaagtg tccagtttct caagacatac aggcccctgc 9360 ccaagagatc cactttattt tcatctcacc cagaatattg aggtgatcag caaggtggag 9420 tggttgggag agggtaaaag caggaaagag agatggggac tcaaacagca gcccatactt 9480 ggaactgcca tagatcctac cagttacttc atggactcca tcaggaaccc acctataagc 9540 cacaggggat gcatccctcc catcttgcca acaaaacccc gaatgctcca aatgcctcac 9600 ccactctttg gctggctccc aagtgcgctc ctgtgaaaag cgagtgagta tctctgcaga 9660 tggcttgcaa gcacatgttg acagctggct ccactctgta gaactggaaa aaagctcaca 9720 tacatgagaa tttcaggaca ctaccctaaa aaaaaaaatg agacttcagc acctggcctg 9780 gctttatgca acctagagaa ggtgatatga tttggctctg tgtccccacg taaatctcat 9840 gtcaaattgt aatccccacg tgttggacaa gggacttggt gggaggtgat tgaatcatgc 9900 gggtggactt ccctcttgct gttcttgtga tagagttgtt atgagatcca gttatttgaa 9960 agtatgtagc atgtccccct tcactctctt gcactcctgc tccaccttgg taagacttgc 10020 ttgctacccc tttgccttct gccatgattg taagtttcct gaggcctccc agctatgctt 10080 cctgtatggc ctgcagaact gaactgtgag ccaattaaac ctcttttctt cataaattat 10140 ccagtcttag gtagttcttt atagcagtgt gagaatggac taatgcagaa ggcatacaac 10200 ctttagaatt tgcccccttg agggaacaag atgtgtgaag caggttcatc catagaaaat 10260 gtctgagaga acctcaaaat ccctaacctg actaactgat gaaagtgttt ctctcctaag 10320 gccagtcagt aaagaccaga gggggtgact gtttctttaa atgcaaaggc agcagcacaa 10380 taattcaaga aacatgaaaa atcaagaaaa catgacacca ccagaagaac acaatcattt 10440 tccaataacc aactccccaa aaatggagat ttacaaattg gtttataatg aattcagaac 10500 aattatgtta aggaagctca gcaaactaaa aggaacacca atagactact ctgtgaagtc 10560 aggcaaacaa ttcatgaaca aaactagaaa ttcaaaaaag agaaaaatta tcttaaaaga 10620 aaacccagaa gttatggagc taaagaatac aatgcatgaa atgaaggagc gtatcaacag 10680 caaagttgat caagcataag aaaaaaaaaa tctgtgaaac tgaagactgg ctatttgaaa 10740 ttattcatca gaggattaaa aaaaaaagaa tgaaaagaaa taaagaaagc ctacaggatg 10800 tataaaacac catcaagaga actaatataa ggattattgg agtcataaag gagaagagag 10860 aaaagggtag aaaacttatt taagaaataa tggctgaaaa ctctccaaat ctaggaaaag 10920 atatgagcat ccaggtatat gaagctcaaa gatccccgta caggatacat tccaaaaaga 10980 cttcaccaaa acacatgata atcaaactgt caaaagcaaa atcaagacga tgaataaacc 11040 accaatcact aagagggaga caggattctt atgttgtcat tattatttac atataatttc 11100 agtaaatgtt attggaaaat ttataatgtt ttaaaaaaag aaatttgaaa gcaccgaaag 11160 aaaagagact catcacatac agggaaccct tttaaggcat tcaagagatt tctcagtaga 11220 aaccttacaa aataggagag agtgggatga actatacaag tgctgcaagg aaaaaaatgc 11280 caaccaacgc tttacctggc aaatctgttc ctcagaaatg aaggagagag aagaactttc 11340 ctagacaaac aaaagctgag gcagttcatc accactagac ctgccttaca agacatacta 11400 aggggagttc ttcaagctga aatgatatgg caatagttag taatatgaaa tgataaacct 11460 cactggtaaa ggaaagtaca tagtcaaatt tagaacactt tgatactata atgatggtgt 11520 ataaataatt ttactgtgct atgaaggtta aaagacaaaa gtattaaaaa aaacccatag 11580 ctgcaatagc ttgtcaatgc atactacagt ataaaaagat gtaaattaga acattaaaaa 11640 catagcatgc aagggtaggg aagtaaaagt gtagttttca tatgtaatca aatttaattt 11700 gttatcagct taaaataaat tgttatacct atgttttatg taagtgtcat ggtaactata 11760 aaggaaaaac ctctagtaga tacacaaaag aaaaagagaa aggaatcaaa acataacact 11820 acagaaaatt atcaaattac aaaggaagac agcaagggag gaacaaagta aaaagagcaa 11880 gaaaaaattt aacataatga aaacagtaag tccttacgtg tcaataatta ctttaaatgt 11940 aaatggatta aattatccaa acaaaaaaac agactggaca aatggatttt agaaacaaca 12000 acaacaacaa acaccgcaca cacacacaca cacacacaaa ccacccagcc ccaactatgt 12060 gctgcctaca agagatttac ttccacttta aggacacata caggctgaaa ttaaaagaac 12120 agaaaaagat attgcatgca gatagaaacc agaagagagg agaggcatct atacttacag 12180 catacagaaa agattttaag ttaaaaacta tatcaaaagg ctaagaaggt caaaatggtg 12240 aagcagttaa ttgttcaaga agacataaaa attgtaaata tttatacacc caatattgaa 12300 gcacctaaat atataaggca aatattaata catataaaag gagaaatata cagcaataca 12360 gtaatagtag tgaacttcag tgcctccctt tcaaaaatgg ataatccaga cataaaatca 12420 ataaggaaac atttaactta aacttcactt tagaccaaat ggatctaaca gacattatac 12480 tgaacatttc atccaacagt ggtagaattc acattcttct caagcacaca tggaacattc 12540 tccaggatag attatatgtt agctcacaaa ataatattac aaaatttaat aaagctgaaa 12600 tatcaattat tttgcaccac aatagtataa cactagaaat caataacaag atggaaactg 12660 gaaatttaca aatatatagc attaacatat tcctgaacaa ccaatgggtc aaagaaaaaa 12720 atcaaaataa ttttgtgaca gcaaagtaga aacacaacat accaaaacat acaggacaca 12780 gcaaaagcag ttctatgagg taagcttata ttgataaaca catttaaaaa aagattttaa 12840 ataaacaaca ttacacctca aggaactaca aggaagaaaa aaaaacaagc cccatgttat 12900 caaagggaag gaactaacaa agatcagaca gaaataaatg aaacatagac tagaaaaaca 12960 atagagacta ttaataaaac ttagagttag ttttttaaaa aataaaatca acaaaccttt 13020 agctagacta aaaaaagaga agactcaaat aaaataaaaa atgaaagagg agacattaca 13080 actgatacca cagacataca aattaagaga aaactatatg ccaacatatt agttaacttg 13140 caatgggtaa atccctagaa acatacaacc tacaaaaact gaatcatgaa gaaatggaag 13200 atctgaacag atcaataatg aataagggaa ttgaatcaat attcaaaaat ctcacaaaaa 13260 gaaaagctca ggatcagatg gcttcactgg tgaagactgc caaccattta aaaaaattaa 13320 taccactctt tattaagctc ttccaaaaaa attgaagagg agaaaacact ttcaaattca 13380 ttataagagg ccagttttac cttgatatca aagatttaaa aagaacactt tgagaaagga 13440 aaattacagg ccaaaaccct tgataaatat agatgcaaaa atgctcagca aaatactagc 13500 aaacctaatt cagcaacaca ttataatggc atacatcatg accaagtgag attcatgcct 13560 cggatgcagg atagttcaat ataatcaaat caacaaatgt tacactactt taacagaatg 13620 aaggataaaa atcatatgat catctcgatg gttgaactag tttacagtcc caccaacagt 13680 gtaaaaatgt tcctatttct ccacatcctc tgcagcacct gttgtttcct aactttttac 13740 agatcaccat tctaactggt gtgagatggt atcttattgt ggttttgatt tgcatttctc 13800 tgatggccag tgatggtgag catttttcaa gtgtctgttg gctgcataaa tgtcttcttt 13860 tgagacgtgt ctgttcatat ccttcaccta ctttttgatg gggttgtttg tttttttctt 13920 gtaaatttgt ttgagttctt tgtagattct ggatattagc cctttgtcag atgagtagat 13980 tgcaaaaatt ttctcccatt ctgtaggttg tctgttcact ctgatggtag tttcttttgc 14040 tgtgcagaag ctctttagtt taattagacc ccatttgtca attttgtctt ttgttgccat 14100 tgcttttggt gttttagaca tgaagacagt gtggtgattc ctcaaggatc tagaactaga 14160 aataccattt gacccagcca tcctgttact gggtatatac ccagaggatt ataaatcacg 14220 ctgctataag ccataaaaaa tgatgagttc atgtcctttg tagggacatg gatgaagctg 14280 gaaaccatca ttctcagcaa actatcacaa ggacaaaaaa ccaaacaccg catgttctca 14340 ctcataggtg ggaattgaac aatgagaaca catggaccca ggaaggggaa catcacacac 14400 tggggatggt tgtggggtgg ggggagggga gagggatagc attaggagat atacctaatg 14460 ctaaatgacg agttaatggg tgcagcacac caacacggca catgtgcaca tatgtaacaa 14520 acctgcacgt tgtgcacatg taccctaaaa cttaaagtat aattaaaaaa aataatgctg 14580 ctataaagac acgtgcacac gtatgttcat tgcggcacta ttcacaatag caaagacttg 14640 gaaccaaccc aaatgtccat caatgataga ctggattaag aaaatgtggc acatatacac 14700 catggaatac tatgcagcca taaaaaagat gagttcatgt cctttgtagg gacatggatg 14760 aagctggaaa ccatcattct cagcaaacta tcacaaggac aaaaaaccaa acactgcatg 14820 ttctcactca taggtgggaa ttgaacaatg agaacacttg gacacaggaa ggggaacatc 14880 acacactggg gcctgtcgtg gggtcagggt agggggaggg atagcattag gagatatacc 14940 taatgtaaat gacgagttaa tgggtgcagc acaccaacac agcacatgtg tgcacatgta 15000 ccctagaact taaagtataa taaaaaataa atcatatcat catctcagta gatttagaaa 15060 agcatttaac aatattcaac atcctttcag aactaaaaac tctcaataaa tcaggtatag 15120 aaagaatgtg cctcaacact ataaaagcca catatgacaa acctggaggt aatatactca 15180 atggtgaaaa gtaaaaagct ttgactctaa gatcagaacc aaaacaagga tgtccattct 15240 caccacttat atttaacata gtagttgaaa ttctagctag agcaattagg caagaaaaaa 15300 ggcacccaag ttggaaagaa tgaagttaaa ttgtctctgt agatgacatg atcttatata 15360 tagaaaacac taaagactcc accaaaatgc tgttttaatt agagcttaaa aaaataattc 15420 actaaagttg caggatacaa aatcagtata caaaaatcag ttgcatttct aaacaccaaa 15480 aacaagttat ccaaaaaatt aagaaaacaa tcctatttgt gatatcatca aaaaataaaa 15540 tactaaagaa taccaaagaa actgaaaata aatggaaata aatggaaaga tagcccatgt 15600 tcatggatta gatgaattaa tactgttaaa atgttcatac tacccaaagc aacctacaga 15660 ttaagtgcaa ttcctactaa aattccaatg acatttttca cagaaataga aaacacactc 15720 ctaaagtttg catggaaccg caaaagactc aaatagatga agcaattttg agcaagaaca 15780 gtaaagctgg agacatcaca ctacctaact tcaaaatttt attaatcaaa acagcatgac 15840 ataaaaacag acagaaaaga ccaatggaac agaatagaga gcccagaaat aaactcacgt 15900 ttatagagtc aactaatatt caacgaaggt gccaagagta cacaatgggg aaagtatagt 15960 ctctacaata aacagcactg ggaagacaat atccaaatgc aaaagaatga aattacaccc 16020 ttatcttata ccatacacac aaatcaaatc aaaattgata aagacttaaa tataagacct 16080 gaaaccatac aatctttagg caaaaactca ttgacattgg tcttggcaat gatttttttg 16140 atatgacacc agaagcacag gcaacaaaag caaacctaaa caagtgggac cctaacaaac 16200 taaaaagttt ctgcacagca aaggaaacaa tcaatcatca gaattaaaag gcaatttatg 16260 aaatgggaga aaatgtttgc aaaccacata tctgataaag ggttaatatc caaaaatata 16320 taaggaatgc ataaaattca atagaaataa acaaacaaat aatccaattt taaaatgggt 16380 gaagaacctg aatagacatt ttttcaaaga agacttacag ataggcaaca ggcatatgaa 16440 aaaatgcttg acatcactaa taatcaggga aatgcaaatc aaagctccag tgaaatacca 16500 cctccaacta ttaggatggc tattatcaaa aactcaaaag aaaacaagct gggggaatgt 16560 agagaaaagg gaaaagaaga tccttataca ctgttggtgt gaatttaaac tggaatagcc 16620 cttatggaaa acagcatgga ggttcctcaa aaaattaaaa atagaactac tatatgatcc 16680 agcaatttca ctattgagta tatatccaaa tgaattaaaa tcactgtctt gaagaggtat 16740 ttgcacactc atatttattt cagcattatt cacaatagcc aagacatgga atcaacctaa 16800 gtgttcatca gtagatgatt agataaagag aacgtggtat atagacacag tggaatctat 16860 ttagtgttca aaaagaagga aatccaactt ttaaaatcct ttaaaaagtt aaactcataa 16920 aaacagagag gagaatggcg gtttccagga actggagggt gggagaatgg ggagatgttg 16980 gtcaaaaggt acaaactttc agttataaaa tgaataagtt ctagagatct agtgtacaac 17040 agcattacta tagttaataa taatattttt tatacttgaa atttgctaag agtaaatatc 17100 aatattctca atacacacaa aacagaacta tctgaaggca ctgatatgtt aattatcttc 17160 attatagtaa tcatttcaca atgtataatg aatatcaaaa caatagtgta catcttaaat 17220 atatacagtt ttgatttgtt aatcatacat caatgaagct agaaaaaatg ttgtaatttt 17280 taaaacaata gtaatataaa ttaggggtga aggaattgac ctatgttgga gaaaagtttt 17340 tgtaaactat ttaaattaat tggtatccat tcaagctaga ttatttttaa ttgttaattt 17400 aattgtaata ctaaggcaac cactaaaaaa gcctttaaaa aaatatagca cttgaggctg 17460 ggcatggtgg ccctcaatta tatatataat atatataaaa tatatattat atatatagta 17520 gatgaacaac aatgggattt aaatggtaca ctagaaaata tctgtttaac aaaaagaaag 17580 caatagtgga gaaatataag aacaaaacca tgtaagattt atagaaaatg aatagcaaat 17640 tggttgacct aaaccctatc ttataattat attaaagata aatgaaataa atactacatc 17700 aaaaggcaga gattatcaga atagagaaga aaaatccaaa ccataattca accttatgtt 17760 atctgtattt agaatattta gagtcaagac acaaatagat agagttccat ttgggcgtga 17820 aaatatttac catgcaaaat gtaattaaaa tagagctaga gcagcaatac taatatctga 17880 caaaatatac tttaacaaaa attgttgcta aagacaaaaa agaacatttt ataataagac 17940 acaacaatta taaacatata caccaaacaa tagagcccaa aatatacaaa gcaaaaactg 18000 ctagaattga agaaagatag aaaaatcaat gattacagtt ggaggtgtca ataccaaact 18060 ttcagtaata cacagaacaa caagtcaaaa gcaaaaagga aataaaaaac tacacattat 18120 catacaacac cttaatacga tatccaacaa tagcagaata cacattattc tgaagtgcac 18180 atggaatatt cttcaggatg acacatatta ggctgtaaaa catatcttaa taatttaaaa 18240 gaattgaaat aatacagcac atattctctg actgcaaaat attaaaccaa ttacagaaga 18300 aaatgtggga aattcacaat gatatggaga tttaaaaata cttcaaagta accaatgaat 18360 caaagaacaa atcacaagag aaattagaaa atattttaga tgaataaaac tgaagaaaca 18420 acataccaaa attttgtggt tgtagctaaa gcagtgcttc aagggaaatg tataacagta 18480 tatccctaaa ttttaaaaaa atctcaatcc aataacctaa tttttcacct taagaaatga 18540 gagtgaaaga gcagacttaa cccaaagtaa acagaaggaa gaaataataa agattagcat 18600 ggagataagt agtgaaaata aaaacaatag agaaaattaa taaacttgaa agttggttct 18660 tctgatatat cagtaaaatt gacgtattat tagtttgacc gagaaagaac aaaagagaga 18720 agattcaagt tactagacat aaatgaaagt atagatatca ccttacagaa attaaaagaa 18780 ttctaacaga atattgtgaa aaagtgaatg tcaaaaaatt aaattatatg agatacacaa 18840 atccctctaa aggcacaaac taccacagct ggtgtaaaaa catgaataca ccatttacag 18900 ttaaaaagac tgaatagata aaaattttaa gaagaaattg agtaagtaat ttaattttca 18960 aactataatc ccaagaccag atgttttcat tggtgaattc taccaaactt taaaaggatt 19020 aatatctatt tttcatacac tctttccaga aaatagaaaa ggagggaaca ctctataact 19080 cactgtatga ggtccgtatt acccttatat caagaccaaa catcataaga aaagaagact 19140 aaagacttat ggtttctgct ctgatatgtt tggaagtcat cactactatt gtcacaagga 19200 aaaatctgaa caaactaaag tcaacgattt cttaaactaa ccatagaatt gaggtaacgg 19260 gcgaaaactg gagatgtagg caaatacaaa aaaaatcaca gtttatcagg agcagaaact 19320 gctgaaacca gcaactcgta tgaacatgtt aagtggtaat tgacaaattt ctggagattg 19380 aatgtggact ggattgagag ttaggaactc ctaagtgccc agtttttgat gaccccacac 19440 acttttgtaa actagacttc caagagcccc agcaagtttc ttacagtgaa gactgcagaa 19500 aaatcccctg atgcttcaga taggaggaag ggaaaagcaa ctattttgaa ataagcccag 19560 gggacaagta gttatttcta aacactctca gagcattttc tttcacacgg cagggggctc 19620 cctgcaaggg aagctacttt gcctgagcct tgtctgatgt aggagaaaag gaattggatg 19680 gctcaagctc catctagcct ttctgattta tataagggaa gcaaaaaata ggttaagaaa 19740 ctcttctgaa agtcacaact cagatttatt ttatatttat ttatttattt atattttttg 19800 agacggagtc tcgctctgtt gcccaggctg gagtgcagtg gcgcgatctc ggctcactgc 19860 aagctccacc tcccgggttc acgccattct tctgcctcag cctcctgagt agctgggact 19920 acaggcgccc agctaatttt ttgtattttt agtagagacg gggtttcacc acgttagcca 19980 ggatggtctc gatctcctga cctcgtgatc cacctgcctc tgcctcccaa agtgctggga 20040 ttacaggcgt gagccaccgc acctggcctc acaactcaga tttaaccata agattataga 20100 acacttctcc tcccaaaaca gagatataga tcaatggaac agaacagagc cctcagaaat 20160 aacgccgcat atctacaact atctgatctt tgacaaaccc gagaaaaaca agcaatgggg 20220 aaaggattcc ctatttaata aatggtgctg ggaaaactgg ctagccatat gtaaaaagct 20280 gaaactggat cccttcctta caccttacac aaaaattaat tcaagatgga ttaaagactt 20340 aaacgttagg cctaaaacca taaaaaccct agaagaaaac ctaggcatta ccattcagga 20400 cataggcatg ggcaaggact tcatgtctaa aacaccaaaa gcaatggcaa caaaagacaa 20460 aattgacaaa cgggatctca ttaaactaaa gagcttctgc acagcaaaag aaactaccat 20520 cagagtgaac aggcaaccta caaaattttc acaacctact catctgacaa agggctaata 20580 tccagaatct acaatgaact cagacaaatt tacaagaaaa aaacaaacaa cctcatcaaa 20640 aagtgggcaa aggatataag cagacacttc tcaaaagaag acatttatgc agccaacaga 20700 cacatgaaaa aatgctcatc atcactggcc gtcagagaaa tgcaaatcaa aaccacaatg 20760 agataccatc tcacaccagt tagaatggcg atcattaaaa agtcaggaaa caacaggtgc 20820 tggagaggat gtggagaaat aggaacactt ttacactgtt ggtgggactg taaactagtt 20880 caaccattgt ggaagtcagt gtggcgattc ctcagggatc tagaactaga aataccattt 20940 gacccagcca tcccattgct atatatatat atatataccc aaaggactat aaatcatgct 21000 gctataaaga catatgcaca ggtatgttta ttgcagcact attcacaata gcaaagactt 21060 ggaaccaacc caaatgtcca acaatgatag actggattaa gaaaatgtgg cacatataca 21120 ccatggaata ctatgcagcc ataaaaaaga tgagttcatg tcttttgtag ggacatggat 21180 gaaattggaa atcatcattc tcagtaaact atcgcaagga caaaaaacca aacactgcat 21240 gttctcactc atagatggga attgaacaat gagaacacat ggacacagga aggggaacat 21300 cacactctgg ggactgttgt ggggtcgggg gaggggggag ggatagcatt aggagatata 21360 cctaatggta aatgacgagt taatgggtgt agcacaccag catggcacat gtatacatat 21420 gtaacaaacc tgcacattgt gcacatgtac cctaaaactt aaagtataat aataataaaa 21480 aaaggctacc taaaaaaaaa aaaaagaaca cttctcctcc caacaccata tcaccacatc 21540 aaccaggact ccagtgtaat agcagtgaat tctaactgaa agaggtgaaa gacactgatt 21600 gtatttaaga aagatcttct aaggaaatcc aaaaatagta ggggagatca aaacaaagat 21660 actagaggaa attgaatatg tgacacctat agctacaaaa aaattaaaca taacatagcc 21720 ctaaccatat aaacataaaa cctcacacaa agacctatta tctgagattc tgttgcctga 21780 tacattgcgt tttatttcaa taaaaaaatt agagggtatg ttaaaaagca ggaaaagtta 21840 gtctaaagag acaaattgag cctcagaagt aggctcagat atggcagaga tttggcaatt 21900 atacctagag tttaatataa atgattaata taataagtgt tctaacagaa aaaggcaaca 21960 tgcaagaacg gatgggtaat gtgatcagca agaaggaaac tctaagaaag aagtcaaaag 22020 gaaatgctag gaataaaaac ctacaagaaa taaagaatgc ctgtgatggg ttcctcagta 22080 gactggacaa ggtcaaagaa tcagtggatt tgaaaatatg tcaacaaaaa ctgccccact 22140 gaaatacaaa agaaaaatag aattttaaaa acgtaacaca atctccaaaa cagtgggaca 22200 attacaaaag atgtaatgtg cctaatgcaa atgacagtag gagtataaag ggagaaagga 22260 atagaaaatc tgaagtaata atggcagaga gttttccaaa attaatgcta aaccacagat 22320 acagcaagcc cagagaacaa caaggaggaa atttagtaaa gcgtctgcaa ccaagtatgt 22380 catattcaga ctgacaaaac caaaggtgaa gagaaaatat tgaaagaaga caaagaggaa 22440 aataaatatc aagaaaatac atacgaaata catcatacat acataagaaa tacatcagac 22500 catacaagca agaagagaat ggagtgaaat gtttaaaatg ttgaaaaaaa aactatcaat 22560 ttgcaattct gtatccagtg agattatctt tcaaaagtga agagggaaat ggcagagaag 22620 tcatctccaa gacctatggt ttcccttcac agaaacactg aaaaatatga acaaaagtgg 22680 tcagaattaa ctttctaaga attctataaa atggtaaaat gtttacacca gtaaagcaaa 22740 tgctgaattg agaaggcaac ttaaaaaggt gaagaaaact tcgtattatt tttatgtgtc 22800 cttgccccac gtccttccct accttagtct tgaagatggc agcccacatt tctactgtgg 22860 ggctctggtt tctgtttcct ggttcaagag ggagaataac agaccttact tttagtcatt 22920 attatttcct tctttctgat ttccttgggt ttattttgct cttctttcta ctttattgaa 22980 atgagaacta agattatgat ttgagacatt tttctaatgt aagcatttag tgctataaat 23040 ttccatctca acactgcttt agtcacatcc cacaaatttt tatatgttgt aatttcactt 23100 tcatttagtt ctatttttaa attttttctt tttatacttc ctctgactca cagattactt 23160 agaattgtgt tgttcagttt tcaaggatat tgtagatttt cctgtttctc tgttgtctaa 23220 tagttctgtt ccattttgta cagatagctc acgctgtatg atttcaattt tttaaaaaat 23280 tgtgctttgt tttatggccc agatatggtc tgtgctgtga atattccatg ttattataaa 23340 gtatgcctgt tatattatta tatatatata atatatataa ttataaagca tgcccgtttt 23400 gtattgttag cagagtattc tagaaatgtc aatgagatct tgttggttga tggtgctttt 23460 cagttctata tctttgctaa tttttttttt ttttgcttag tagctatatg agattctgag 23520 agaggaaatt gaagtctcca accataattg tggatttgtc tatttctcct atcagttcta 23580 tcagtttgtg catcacatat ttgaggctct gttgtttggt gcatacacaa gtggaatcat 23640 tgtgccctct tggtggctta ttttatgatt atatagtgcc tatctttgtg gtatttttat 23700 ttgctcttaa atctactttg tgttatattc atatacccat tcttttttaa aaaaaattgt 23760 ttgcgtgata catcttttcc attcttttaa tctcagccta tctgtgccat tgaatttgaa 23820 gtgagttttc atatagagaa catattattg aatcatcatt ttaaaaattc cttttgccaa 23880 tcttttttat actgaggtaa aattgacata aaatttatca ttttaaagtg tacaatacag 23940 tggcatttgg taatacacat gttatgcaac gttaactcta cctggctcct aaatgttttc 24000 atcatcccca aaaggaaact tcatactcat taagcagtta attcccattc cttctctcgg 24060 ccactggcat ccgcaaacct acttttctgt ctctatgaat ttacctatta tggatatttt 24120 gtataaattg aattatacaa taagtgacct ttatgtttgg cttcgttcgc ttcgcatact 24180 atttttcgat attcaaccat gttgtagtat gtatcagttt tatttgaata actcaattct 24240 ttttgttgta tagctaaaag ttgattccta ggtcataatg ataattctat gtttagttta 24300 ttgaatagct gccaaagttt ttccacagtg gctctgtcat tttaaaatcc cactagcaat 24360 ggatgagagt tccaatatct ccacatcctt accaatattg ttattttata tttttataat 24420 tataattttc ctagtgaata cgcaatggta tctcattgtg tttttggttt gcctttccct 24480 aatgactaat gatgttgagc atcttacaat gtacttgtta actatttgtg ttctttagag 24540 aaatgtctat tcaagtgcct tgtccatttt aaaaatcgag ttgtcttgtt gacttatgag 24600 ttctttaata cagtaaacgc ttatcagata tgatttataa gtattttaac ccattctgaa 24660 ggtcaccttt tcacttttgt ggtagaccat tatgcacaaa ggttttaatt ttgataaatc 24720 caatttatcc gcttttgttg ttgtttttgt tgttcgtgct tttgcaaaac ctagtgtcat 24780 gaggttttct cattatcttt ggagaatttt atagtttggg tctatacatg tagattattg 24840 atctaatttc cattaatttg tgtgtatgct acgaggtagg ggtccaaatt caatttttgc 24900 attgaattga aaattcatat tttcagtttc aaatttcaac tgcatattca gttgttgcag 24960 cacaatttgt tgaagagatc attctttacc acagggaatg atctgggacc cttgtcaaaa 25020 atcaattgat catagatgta tgggattatt tcagacttta gatcttgttc catgaatatg 25080 cctattttta tgccagcact gcagtatttt cattactgta gctttatcat aaattttgaa 25140 atcaggaagt atgtatcctc caagtgtgat tttcatttgc tagagtgttt tgactatttg 25200 gggtctttgc aattccatat gaatttcaga attggctttt catttaaaaa aatggtagtt 25260 gagattttca taggaattat attgaatcta cagatcactt tgggtagtat tgccatctta 25320 acaatattgt attccaatcc ataaacacgg atgtattgcc attcatatct ttttttcttt 25380 tctttcggca acatttagta tatgacactt gtaactcctt ggttaaattt atacctaagc 25440 attttatcct ttctgatgct gtttaaatgg aattatttta ttaatttctc ttttagatgg 25500 cttgttgcag gtgtatagaa atagaactga ttattgtgct tttattgaat tatctgaaac 25560 tttgctgcat ttattaactc tagtaggttt tttttttctt taaagttgtc tatatatctt 25620 gctctgtgaa tagataattt tacttcttga tctccaatat ggatgccttt ctttcttttt 25680 cttacctaat tgctgtagct agaattttca gtataatgta tgatagaagt tgttcacaac 25740 tatccttgtc ttctttctga tcctaggggt atagctttca gtctttcacc attaagcaca 25800 atgttagctg tggggttttc ttagatgcca tttaatatat taaggaagtg ctctgctatt 25860 tctaattggt tgagtatttt tattataaaa tggtgttaga ttttatgact ttatgtactg 25920 cataattgag attatcatgt ggtcttttca ttcgattaat gtggtatatt ttatgatttt 25980 catatgttga tccaccttta tattcttggg gcaaatccca ctgtgtacac gggtttttta 26040 gggtctccta attttcttca ttctttttct tttctctccc tgagactgaa taacgttaac 26100 tgacctatct tcaagtttac tattttttct tctgctgttc aaatctgctt gaacctatag 26160 agtgaatttt tcattttact tattgaactt ttcagctcca aaatttctct ttggctactt 26220 tgtataatat ctatctctct atagatattc tctatttgga aagacatttt tctcctggtt 26280 ttctttactt atttgtattt tttaaagtct ttaagcatat ttgagacagt tgatttaagt 26340 atttgtgtac taagtccatt gcctaagctt ttgcatagag attttatatt aatttctttt 26400 ttttctgtga acaggtcttt tttttttttt tttttttttt ttttttttta gaaaactgga 26460 cattttgagt agtataaacg tggctatttt agaaataatt ttcctccctc cttaggtttt 26520 gtttccactt gttgcatgtt gctgttgttt gctcattagt gacttttcta aagtattttg 26580 aaaagtctgt gttcttgatc atgtgggtcc attgaattct gtattctgtt aatttcatag 26640 tcagctagtg ttctgaaagt tcccttaagt gcatagagcc aataaaagaa aaagaaaaga 26700 aacacagaaa aagaaaagag gaaaaaagga gggaaagaga tttaaaaaaa taatgtcggt 26760 tgggcatggt ggctcatgcc tgtaatccca gcacttttgg gaggccgagg caggcaaatc 26820 acttaaggtt gaccatcctg gccaacacgg agaaaccttg tctctactga aaatataaaa 26880 ttagccgggc atggtggcac atgcctgtaa tcccagctac tcgggaggct gagaggtagg 26940 agaatcactt gaactcggga ggtggaggtt gcagtgaact gagatcacac cactgcactc 27000 cagcctgggc aacaagaatg aaactccatc tcaaaaaaaa ataataataa taatgccttt 27060 gccgatttgc tctgtgtttg ggccctcatt caatgcctag tcaggccatt tacaactctc 27120 tcttaacttt cactacctgc ttgtgtactg actgaaggcc acctataggt gaaagcttaa 27180 catcatctca gatctttttg gaccatgaat cctaccctgg gtatgcacat gatcttctta 27240 atttcccagt agatgcaaga gttttagtgt tttaaaagtc cttattccct catctatctt 27300 cttttctgac ctttttcagt ctgcttattg ttcatctgaa ctgacatcct ttgccccaag 27360 cggctgtggc aaaaactttt acctttaaat gctttcacca caagccactt gggaagctgc 27420 cccagacctg ggactgctct gaccctgatg aaacaaagac aagaccttgt acagccaggc 27480 agccataaga caagtccata cccaaaccac agttctttca gaataaggtc tatattggat 27540 tctctggccc tagtaaccag catgagtctg ggcttgccat cttcatggcc acttgtctta 27600 gtttgctagg gctgccataa caaaatatga gagactgagt ggcttaaaca agagaaattt 27660 attttttcac aattctgaag accagaagtc cattactctg aaatctctct ccttggcttg 27720 cagatactgc cttcttgccg tgtcctcaca cagccttttc tctgtgtaca catccctggt 27780 gttttttaag cctgtccaaa ttttctgttc ttctgaggac accaatcaga ttggattagc 27840 gaccacccat atgatcattt taccttaagt acctcttcaa aggtatcaga gtagtatatt 27900 tgctacagtt gatgaacctg catacaacat catcacttga ggtctgcagt ttacattaga 27960 gttcatcgtt agtgttatat attctagggt ttgttttgtt ttgagacaga acagagtctt 28020 gctgtgttac ccaggctgga gcgcagtggt acaatctcat tgctacctct gcttcccaga 28080 ttcaagcaat tctcatacct cagcctccta agtagctgga actacaggcg cacaccacca 28140 tgcccagcta attttcgtat ttttagtgga gatggggttt caccatgttg gccaggcagg 28200 tcttgaactc cttgcctcaa gtgatctgcc cgcctcagcc tcccccagtg ttgggataac 28260 aggcatgagt caccatgcct ggccttattc tatgggtttt gaaatgtata atgacatgta 28320 tccatcgttg tagtattaga tagaatagct tcattaccct aaaagtcttc tttgcactgg 28380 gttgagtttt aaaagctctt tgattatttt atgacagttc cttattagat atatcttttg 28440 caagtatttt tatcagtctg tggttatctt gtcttttaca gagcagtaat ttttaatttt 28500 aataaaatcc aatttgtcaa ttacttatct catatgactc tggtgttaca tctaaaatgt 28560 taccaccata ctcaaggtca cctaggtttt ctctaggaat tttatggttt tgcattttac 28620 atttggtgta tgacccattt gaagttaatt tttgtgaggt tgtaaggtct gtgcctagat 28680 tcattttttt tttttttggc atgttacttc agtattcata agaaacattg ttctgtaatc 28740 ttctttctta tagtatctta gtcttgcttt agtttttggg caatgctggc ctcactgaat 28800 aaattcaaag tgttccctcc tcttcaatta tttggaaaag tttgagaaag actattgtta 28860 actgttttct aaatttttgg tggaatttac cagtgaacca actggtccta ggcttttctc 28920 cagtaggtgg ttttgattat gctttcaatc tctttacaag ttacacatct atacagactt 28980 ttataattca gtcttggtag gttgtgcgta tttaggaatc tgaccacttc atctaagtta 29040 tccaattagt tggcatgcaa ttattcgtag ttctctgaat aatcattttt atttccacaa 29100 aattggtaat atcccagttt ccatttttta tttcattgaa tcttcttttt tcttagctaa 29160 tctagctaaa tgtttgccaa ttttgttgat cttttggaag aaccaacttt tgatttatta 29220 attttctcta ctctttttct gttctttata ttatttattt ccacactaat ctttactatt 29280 ttcttccttc tgttggcctt taattttttt tttttaattt ttaaggtgta aatttaggtt 29340 gagaaatttt ttaaatgaaa gcatttagag ctataaattt tccttctggt gttcctttca 29400 ctacctgcca taaattttga tatgttgagt ttttgtttgt cttggagtat tttctaattt 29460 gtcttctaat ttcttccttg acctattggt tatttaaatg tatttaattt ttgcatattg 29520 tggatttccc agttttcctt ctgttattga tttctagttt tattccattg tgatcacaga 29580 agatattttg tataatcgca gtctattaac atttattaag tcttgtggcc taacagagga 29640 tctatgttgg agaatgttcc aagtgcaatt gagaatacta ttctggtgct attaggtgaa 29700 gtattctcta tatgtctgtt aagtccaatt catctatagt gttgacgttt cctgttcctt 29760 actgattttc tgacttatta ttctatccat tattaaaagt ggagtggtaa agtctctatt 29820 attgtagaac tctctgtttt tcaagtctat caatatctgt ttcatatatt ttggagctct 29880 gtttgctgca tatgtgttta caattgttat atcttcttgg caaattgacc agtttcatca 29940 acataaaata taattcttat tgtcttctaa cagtttattt ttctttttac ataaagccta 30000 ttttatctga tcttagattc cctcacactc caccccagca cgcttttggt tacatttaca 30060 taatatatct tttccatcct ttcattttca acctgtttgt gtctttagat ctaaagtgaa 30120 tgtcttacag acagcataag ctatgtcatt aaaaaaatcc attctgctta tctctgcctt 30180 ttgactgggg agtttaatcc atttgcattt aaagtaatca ctgatcatta aatactttca 30240 gtattttgtt gttttatgta tgtcttataa ctcttttgct cttcatttcc ttcaatattg 30300 cctttgtgtt tagcttatct ttttgtgtca cactttgatc cccttctcat ttctttttta 30360 tattttcttt gtggttacca ggaggacaat gtatcaactt ttaaagttat tacaatttta 30420 tttttttaaa tctctcccat tcggggattt taggaaggtt aaataataat gtaaatgaga 30480 tacctagaac aatataagca ttcaggaatt attaactcaa ttccaatcct tcctccacct 30540 ccacctcttt ctctgtgaga ttatagaaaa gatgacaaaa aggatgtttt ctgagccctt 30600 taattgttga gaatgatctt tgagaaaaag aaaaaaaatg aaagcactag gaatgtacaa 30660 cagcctggaa gtataattaa gtgtaaatta aatagataaa agttataagc agaggaaagt 30720 atagtagaac tcagtattta aaagagaatc aatgtgaaaa ttatataaat ttatgtaaaa 30780 taaaactacc agacaaatct gatatcctta ggatttttct ttctttcatg tgatttctaa 30840 ttgctacata tgacactaaa ccattgatct gagctgtaag agaaactgga aattgttctg 30900 ttatcttttg taagatttct agaacatttt gccctcagac ttaaatgcca acgtatttct 30960 cacttattgt ttactgcttt tggatttaca tatgatttga ttctttctta tctcttatcc 31020 ttacaatgta attcaaactg atgccaattt aagttcaatt gcgtacaaaa actctactcc 31080 tatgcagctc cgccccatct aatttacatt attgatgtcg caaattccat ctttgtacat 31140 agtttacata ttaacatgga tttatacatt tttatgtatt tggtttttaa atcctgtaga 31200 aaataaaaag tcaacacacc aatattaaaa taatactggt ttttatattt gtccatgtgc 31260 ttacctttat cagtgttctt tacatcttta tacgggtttg agttactgtc ttgtgtcctt 31320 tagttccaac ctaaagaact ccctttagca tttttatagg gcaggtctag tggtaatgaa 31380 ctctctgagt ttttatttag ggatgtctta atttctagct cctgtttgaa gtaaattttt 31440 ctggatatac aattctctgt tgattgattt ttgttcattt tcccttcagc tcttttaaat 31500 acattatccc actttcttct gccttccaag gtttctatta acaaaattca gcttataatc 31560 ttattaaaga tctcatgtac atgagtggct tctctcttgc tgttttcaag attctgtgac 31620 tttggtttct gatagtttaa atataatgtg tcttattgtg ggtctctttg gatttatcct 31680 agagtttctt ggtcttctta cgttggtata tccatgtatt tcaagacatt tgagtagttt 31740 tcagccatta tttcttcaaa caatctctcc tctttgggga cttccatttt acctatattg 31800 gttcttttga tggtgtggca ccagtcccct agactttgtt cacttttttc cagtctttta 31860 tttctgcttc tcagactcaa cagcttcaag tgttctgtat tcaagtctgc tgactctttc 31920 ttcttccagc tcaaatctgc tgttggatcc ccccttgtaa aatttttaat tccattttag 31980 tgtttttcaa gttaagtatt tttattaggt tcctttttat aatttctttt tgttgatatt 32040 ctcattttat tacacataat ttgtctgatt tccattagtt tttttctttg ttttccttta 32100 gctctttgaa aatatttaag acattttaaa agtctttatc caagttcaat ttctatggtt 32160 ctgtagagat attttctgcc agtttatgtt cttcttttcc atgggccatg ttttcctgtt 32220 tctttgtata ctttctaatt tttggttgaa aactgagcat ttgaaaatag agccaacttt 32280 cccagtttct gcagagagtc tttatgccac agtattcgtt cactgattaa ctgggtatat 32340 ctaagcttag ggagcagctg agtcaaaagt ttaaggtctt ctcaggtctt ttctgagtat 32400 acatgtttcc tatgcctgtg tgaaatgttc tcaatttccc tatataaaca gctacttctt 32460 cttttttttt tttttttgag atggagtctc gctctgtcac ccaggctgga gtgcagtcat 32520 ctcagctcac tgcatcctcc acctcccagg ttcaaacaat tctcctatac aggtgtgtgc 32580 caccacgtct ggccaatttt tgtattttta gtagagacag ggtttcgccg tgttggccag 32640 gctggtctca atctcctgac ctcaggagga ttacaggctt gagccacagt gtccagccta 32700 aacagctact tttgaatgct ttaatttcct gaatagtctc aacccagttt ttccttgagg 32760 tcttaggtgg tccattgtat gtctccaccc atagttgctt gccccaggca tctgtgggtc 32820 tgtggtacca ctgcagcttt caccacctgt agctgccacc tttccctatc tgagatccag 32880 gttaggtgag agagatcatt ccttcacgca gtcccatgac aggttggaac atttcaaata 32940 aggtctgttc tgctcctctg gttgaaggga gaaaattggg aaccggtttc ccaccttcta 33000 caaaccaaga tctcatgttg ccacgggagt ggcagggcaa gtgcaagtga aaatgccata 33060 caattttcta ccattttgaa cgcgggtttt tcttcaatgg tcatttgctt ggttgctgta 33120 ggcctttcac tgttttccag agctcccata agattacttt agccagtttt ttgttctttc 33180 ctgatgcttc cctggcagag taagggttgg aacttccacc attttgctga ttcataactc 33240 tgtagtcagt tttaaatata ttgatacttg agtttgtttt atggcccaga atatggtctt 33300 ggtaaatgtt tcacatatac tcagaaagaa tgtgtattct gatgttgtta catgggctgt 33360 tctataaatg ttacttaagg tggttaataa tgttgctcaa gtcttctata ttcttgctga 33420 ttttctttta tttatttatt ttattttttt tattatactt ttaagttcta gggtacatgt 33480 gcacaacatg caggtttgtt atatatgtat acatgtgcca tgttggtgtg ctgcatccat 33540 taactcatca tttacattag gtatatctcc taatgctgtc cctccctgct ccccccaccc 33600 catgacaggc cccagtgtgt gatgttcccc tttcctgtgt ccaagcgttc tcattgttca 33660 attcccacct atgagtgaga acttgcggtg tttgtttttt tgtccttgtg atagtttgct 33720 gagaatgatg gtttccagct tcatccatgt ccctacaaag gacgtgaact catccttttt 33780 tatgactgca tagtattcca tggtgtatat gtgctacatt ttcttaatcc agtctatcat 33840 tgatggacat ttgggttggt tccaagtctt tgctattgtg aacagtgctg caatgaacat 33900 acgtgtgcat gtgtctttat agcagcatga tttataatcc tttgagtata tactcagtaa 33960 tgggatgggt gggtcaaatg gtatttctag ttctagatct tgaggaatca ccacactgtc 34020 ttccacaatg gttgaactag tttacagtcc caccaacagt gtaaaagtgt tcctatttct 34080 tcacatcctc tccagcacct gttgtttcct gactttttaa tgatcgccat tctaactggt 34140 gtgagatggg atctcattgt ggttttgatc tgcatttttc tgatggccag tgatgatgag 34200 cattttttca tgtgtctttg gctgcataaa tgtcttcttt tgagaagtgt ctgttcatat 34260 cctttgccca ctttttgatg gggttgtttt gttcttgtat atttgtttga gttctttgta 34320 gattctggat attagccctt tgtcagatga ggagattgca aaaattttct cccattctgt 34380 aggttggctg ttcactctga tggtagtttc ttttgctgtg cagaagctct ttagtttaat 34440 gagaccccat ttgtcaattt tggcttttgt tgccattgct tttggtgttt tagacatgaa 34500 gtcctcgccc atgcctatgt cctgaatggt attgcctagg ttttcttcta gggtttttta 34560 tggttttagg tctaacattt aagtctttaa tccatcttga attaattttt gtataaggtg 34620 taaggaaggg atccagtttc agctttttac atatggctag ccagttttcc cagcaccatt 34680 tattaaatag ggaatccttt ccccatttct tgtttttgtc aggtttgtca aagatcagat 34740 ggttgtagat gtgtggtatt atttctgagg gctctgttct gttccattgg tttatatctg 34800 ttttggtacc agtaccatgc tgttttggtt actgtagcct cgtagtatag tttgaagtca 34860 ggtagtatga tgcctccaga tttgtccttt tggcttagga ttgtcttggc aatacaggct 34920 cttttttggt tccatatgaa ttttaaagta gttttttcca attctgtgaa ggaagtcatt 34980 ggtaacttaa tggggatggc attgaatcta taaattacct tgggcagtat ggccattttc 35040 acgatactga ttcttcctat ccatgagcac ggaatgttct tccatttgtt tgtgtcctct 35100 tctatttcgt tgagcagtgg tttgtatttc tgcttgaaga ggtccttcac gtcccttgta 35160 agttggattc ctaggtattt tgttctcttt gacgcaactg tgaatgggag ttcactcatg 35220 atttggctct ctgttagtct gttactggtg tataagaatg cttgtgattt ttgcacattg 35280 attttgtatc ctgagacttt gctgaagttg cttatcagct taaggagatt ttgggctgag 35340 acgatggggt tttctaaata tacaatcatg tcatctgcaa acagggacaa tttgacttcc 35400 tcttttccta attgaatacc ctttatttct ttctcctgcc tgattgccct ggccagaact 35460 tccaacacta tgttgaatag gagcggtgag agagggcatt cctgtcttgt gccagttttc 35520 aaagggaatg cttccagttt ttgcccattc agtatgacat tggctgtggg tttgtcataa 35580 atagctctta ttattttgag atatgtccca tcaataccta atttattgag agtttttagc 35640 atgaagggct gctgaatttt gtcgaaggcc ttttctgcat ctattgagat aaacatatgg 35700 tttttgtctt tggttctgtt tatatgatgg attatgttta ttgatttgtg tatgttgaac 35760 cagccttgca acccagggat gaagcccact tgatcatggt ggataagctt tttgatgtgc 35820 tgctggattc agtttgccag tattttactg aggatttttg catcaatgtt catcagggaa 35880 attggtctaa aattctcttt ttttgttgtg tctctgccag gctttggtat caggatgatg 35940 ctggcctcat aaaatgagtt agggaggatt ctctcttttt cctatttact gtacatttat 36000 tccaccagtg actaaaacag gtgtatcaat aaaatctgtt ccctcaggtt ttgcttcagg 36060 tattttgagg gtctgttatc aggtgcataa acaagattgt tatgtcctat tcttaaatta 36120 atctccttat aattatgaag ttaatttttt ttttcttgag atgcagtttt gctctgtcgc 36180 ccaggctgga gtgcagtggc acaatctcgg ctcagtgcaa cctctgcctc ctgggttcaa 36240 gcatttcttt gcctcagcct cccgagtagc tggggttaca ggtacctgcc accacgcccg 36300 gctaattttt ttgtattttt agtagagatg gggtttcacc atcttggcca agctggtctt 36360 gaactcctga actcttgatc cacccacctt ggcctcccaa ggtgctggga ttacaggtgt 36420 gagccactgc gcctggacct ggcccgaagt aaacttcttt acccttgcta atgatctttg 36480 ctctgaagca tgctttgctg gtattaatat agtcattcct tctttctttg attcatgttt 36540 gcagggtata tctgtttcca ttcttttact tttaacctat tgtctttata tttaaagtgc 36600 atttcttgta agtataattg gtttcttaaa atccaattat ctgcctttta aatgtcattt 36660 ttatatgatt tgcataaata tgattattat tacagctaaa ttgaaatctg tcatcttgct 36720 atttggtttc tatttatccc atttttttcc cctctttttt tgctttcctt gagattgaac 36780 attgtattag ttttctaggg ttgctgtaag aaagtgacat aaagtggatg gcttaaaaca 36840 acagaaattt attgtttcag tttggaggct agtcatctga aaccaaggtg tcatcagggc 36900 cgtattctct ctgaaacctg tagggaagaa ttctttcctg cctgttctag cttctagcat 36960 tttccagcaa ttcttggcat tcctttgctt gtagatgtat ccctccaatc tctgcctcta 37020 tcataacata gccatcttct ccctttatct gtctattctt ctcatcttat aagaacatta 37080 attactgaat tggggcccag catagattag gcctaatctc atcttgaata ggttacatct 37140 gccaaagatt cttcttccaa ataagatcac ttttacagct tttacaggta ctgagagtta 37200 gaacctcaat atatcctttg gtggggaccg acctcttacc cataaaaagt attttatatg 37260 attccatttt atctcctttt taggttatta actacaattt ttttttcttt tttttgagat 37320 ggagttttgc tcttgtagcc caggctggag cgcgattttg gctcactgaa acctctgcct 37380 cccgggttca agtgattgtc ctgcctcagc ctcctgagta gctgggatta caggcatgtg 37440 ccaccgtgcc tggccaattt ttgtattttt agtagaaaca gggtttcacc atgttggcta 37500 gggtgggtct caaattcctg accttaggtg atccacccac ctcggcctcc caaagtgctg 37560 ggattacagg cgagagccac cacgcctggc tttataattt ttttttaatt cagtggatgt 37620 tttagggttt atagtataca tctttatcac agtctagctc caagtgatat atccctttat 37680 gtatagtaca tgacccttac agtagtgcat ttccattttt cctctctggc atttaggcta 37740 ttgcacacac atacactcaa ttcatccctt tgtgtagatc cgtatttcca gctgctatct 37800 tttgcttctg tctgaaatat atgtatgatt tcttttatga ctattttgag aaatttggtt 37860 atgtgcattt gtctattttt cttatgtact tttagctcat caatcttaag tctgtgagtt 37920 tatagttttt aaaaacaaat ttgaaattat ttggctatta tttcctcaaa tatttttttc 37980 tgccgcccct gctttccctt tccttaggga tctctgattt ccacctatat tactctgatt 38040 gaagttgttc cacgtctctt ttgaaaatct ctgaaaaatc ttttatcatt tggataatct 38100 gtatttgtac atcttcaagt acattaatat tttcttttgc aatgtttaat ctgctgttaa 38160 tcccatgtag tggattcttc atctcaggta ttgctgtttt aatctctaga aattccattg 38220 aagtcttact tgatgaaaaa ggcagataaa aacaaatgtt ggcaaagata tggagaaatc 38280 agaatctgca cacactgatg atgggaatgt aaaatggtca aggcaatttg gaaagcagtc 38340 tggcagtttc tcaaaaggct aaacgtagtt cccatatgac agcaatcatt catctaggta 38400 tatactccag agaaataaaa acatatccac accagaactt gaacattaat tttcatagca 38460 acattattcc taggggttta aaatttttta cattattttt atttaaaata gagacagggt 38520 ctcactacgt tgcataggct ggtctggaac tcctggaatt aagcattcct cctgcctttg 38580 tcctgttttc tccactggaa aagaataaaa ctttgtacac ttggactaac aactcccgat 38640 tccctccttt accaacatgc cccacagcct ctagtaactt actctctact ttcatgaatt 38700 caactttttt aagattccac atataagtga gatcatacaa tatttgtctt tctgtgcctg 38760 gcttatttct cttagcataa tgtcctccag attcatacat gttgtcttaa atgacaggat 38820 ttaccttcct ttaaaggctg actagtactt cattgtgtat atgtatcaca ttttctttat 38880 ccacttatct gttgatgggc acttaaattg tttcaatgtc ttggctactg taagtaatgc 38940 ttcaataaac atgggaatga agatatccct tcaacatatt gatttctgtt cttttggata 39000 atactcagaa gtgagattac tggatcatat ggttgttcta tttttttcag aaacctccat 39060 actgtttttc atagcggctg tactaattta cattcccact aacaatgcat gagttcactt 39120 ttctggacat cctccccaac acttgttatc tttcatcttt ttcataaaag ccattatata 39180 ataggtgtga agtgacatct cactgtggtt ttgatttgca ttactctaat aattagtgtg 39240 agcatttttt ttttttcatg taccgaatgt cttttgagaa aggtctcttc attcctttgc 39300 ccattttaaa atcaggtggt tttcttgctc ttgagttgtt tgagttcctt atgtatttta 39360 gatatttacc catttccaga tatatcattt atattttttc ctattctttg agttccctct 39420 tcactgtgtt gtttccattg ctgtgcaggt cttttatttt gatgccaccc catttgtcta 39480 tttttgccat gcttttgcag tcatatccaa aaaaatcatt cccaagacca atgctgtgga 39540 gatttccccc tatgttttct tcagtaggtg tacagtttta ggtcttatat gttaagtttt 39600 aaatctattt ttttatatgg tgtaaataag ggtctaattt aattcttttg catgtggata 39660 tccagttttc ccaacaccat ttattgaaga ccctgtcctt ttatactttt cagtatgcag 39720 atcttttacc tccttaaatt tacacctcag tatttaatat ttgttgctat tatgagattt 39780 tcataatttc cttttcagat agctcattaa tagtagatgg aaacactact gatttctgta 39840 agatgatttt gtattacgga actttactga gtttgtgtat cagttctacc aggttttagt 39900 tttgttctgg tggagacatt acagtttttt gtatatggtt atgtcatcag taattacaga 39960 tgatttaacc tattcctttc ctattaggat gccttttttt tctttctctt gtccaactgc 40020 tctggttagg acttctagta ctatgtcaaa aagtgatgag ggtcgtacat ggcctccata 40080 cctaatctgt tgagagtttt taccatgaaa ccaggttgaa ttttgtcaaa tgctttttct 40140 gcatccattg agatgatcat atgatttgat ttacaccctc cattttgtta tgtggtatat 40200 cacacttttt gatgtgcata tgttgaacca cccttgcatc ctaaggataa atcccacttc 40260 atcatggtga atcattcttt gtattcgtga atccagtttg ctaatatatt gttgaggatt 40320 tttgcatcca tgttcatcag ggatattact ttgtaagttt ctgtccttaa agtgtctttc 40380 tctggcttta ataacagtgt aacactaccc ttgtaaaatg aatttagaag tattccctct 40440 gcttcattgt tttggaaaag tttgagaatt tttattagtt ctttaaatgt ctggtaaaat 40500 tcagtagtga agctgcctaa tcctgggctt tcctttggtg ggatactttt tattactggc 40560 tcaatctctt ttcttgttat tggcttattc agatttgttt cttcatgatt cactctttgt 40620 aggttgtata tgtctaggaa tttattcatt tctttaggtc atccaatttg atggtgcata 40680 acttcatagt agtttcttat aatcctttgt attttggtga tatcagtagt aaatgtctcc 40740 tctttcattt ctgatcttat ttgagtactc tttttttctc ctagtctagg taagaatttg 40800 ttgattttat ctttcaaaaa aaaaaaaaac caactcttag caactcttag ttttgttcat 40860 ttttttccag tctttatttc aactgtgatc tttgttactt acttctttat gctaactttc 40920 gggcttagtc tgttcttttc ctagttcctt taggtgaaaa gtgagattgt gatccttctt 40980 ctttattggc gtaggtttgt atcgctataa atttccatta ggactgattt tgctgcatca 41040 cataagtttt gtttccattt tcatttgtct caaggtaatt ttttatttac tttttgactt 41100 cttctgtgaa ctattagttg tttgggagca tattgtttaa tttccacata ttgctgtatt 41160 ttccaccaga attgattctt gttcttgatt tctagtttca cgccattgta atcagaaaag 41220 ggatttgata tgatttctgt ccacttaaac ttaagattag ttttgtggac taacatatat 41280 cctggagaat gttccatggg catttgagaa caaaatgtat tttgctgctt ctggatggaa 41340 tgtttcatat atgcctgtta agtccgtttg gtctaaagtg taattgaaat ccattgtttc 41400 tttattgatt ttctgtctag gtgatcaatc tgcccatggt gaaaagtaga gtattgaggt 41460 cccgtattat agtattgcag cctatctccc tcttcacatc atttaaaaat tgctttatgt 41520 atttaggtgg gtcaatgttg ggtgcatata cttttacaat tgttatgtct tcttggtgaa 41580 ttaatccctt tatcattata taacaaactt ctttcttttt atagtattga cttaaagtct 41640 attttgtctg atagaagtat agctacccct gctctcaatt tccatttata tagaatatct 41700 ttttccatcc cttcactttc agtctatgtg tatgtttagt agaaaagtga atctcttgcc 41760 gggcgcagtg gctcactcct gtaatcccag cactttggga ggccaaggcg gcgggatcac 41820 cagaggttgg gagttagaga ccagcctgac caacatggag aaaacctgtc tctattaaaa 41880 atacaaaatt agccaggcgt ggttgtgggc ccttgtaatc ccagctactc gagaggctga 41940 ggcaggagaa ttgcttaaac ccgggaggtg gaggttgcgg tgagctgaga tcatgccatt 42000 gcactccagc cttgacaata gcaaaactcc gtctcaaaaa aagaaaaaga aaaagaaaaa 42060 aaagtgagtc tcttataggc agtatgtggt tgtgacttaa aaaaaaaaaa aaatccattc 42120 tgtcattcta tgtctttttg ttggagaatc taatccgttt acattcaagg taactattgg 42180 taagaaactg ctagtgtcat tttgtaattt gttttctgat tgttttgtag gtcccttgtt 42240 tcttttttcc ctattgctac cttcctttgt ggtttggtgg ttttctgtgg tggtgtgctt 42300 tgaatccttt cttttatagt atatgcgatt accattgtat ttgctgtaag gctaacttaa 42360 aacattttat ccttaggcta ctttaagcga taaaaacttg cctttagttg catacaaaaa 42420 ctctacgctt tcacaacccc cccgcctttc gtgattttga tgtcaaagtt tacacttttt 42480 taaatttgta tctcttattg tagctacagt tacaattact tcttgtagct acaacttatt 42540 gtagctacag ttgtttttaa tagtttcatc ttttaaacct cctaatagga ataacattgc 42600 tttacctgcc acctttacaa tactagagaa ttctgactat gaattactta taccatttag 42660 ttttttactt ttatgtttct cattaactag cagtctttta tttaagccta aagaactccc 42720 ttttagtaat tccagtagag caggcctagt agtgacaaac tcccttaggc attgtttatc 42780 tggaaaagtg tttatttctc cctttgccaa gtaaagtatt cttaattaac agctttgttt 42840 ccttcagcac tttgaatata ccatcccact ctctactggc ctgtaaggct tttgctgata 42900 aagccactga atctgtattg gggctacctt gaatgtgatg tttcttatct ttgctgcttt 42960 cagtattctt tgtctttgat ttttgataac ttggttgtga tgtgtcttgg tgaactcttt 43020 aggttgaatc tgatcggtga cctcagcttc ctgttcctga attttgtcat cttttctcag 43080 atttgggaat ttttcagcta ttacttcctt aaatatgctt tctaggcctt tttctttctt 43140 ttctccttaa ggacctccta ttatgcaaaa gttagctagc ttgatgtgtc ctgtaattct 43200 tataggcatt cttttttgtt tttgtttctc attggataat ttcaaatgtc ttacctttga 43260 gctcattgat tcttctgctt gatcaagtct gctgttgaag cgttctactt agattttcag 43320 ttcagttact gtattcttta tctttagaat ttctattgtt tttgtttata tttgttaaac 43380 ttctcattct gttcagatgt tgttttccaa atttcatttt tctatccata ttttcttgta 43440 ctttgttgaa cttaagagga ttagtctaaa ttatttgtca tttcacaggt ctccatttct 43500 tctgagtctg ttactggagc tttcatatcc aatgtacacc agaaactttg ctaattccac 43560 agtaaatgtt agaaatgggt ttttattgat aaaatcagtg gcttgctaat tagtatgtta 43620 gaagctggct tgcattggtg aagttgaggg tattcgatat acgtatcccg gctaaaatac 43680 ttctaaagaa cctctccagc tttgcaagaa tagagtatag gaatctgagg aggcctttaa 43740 catggccctc agaaaggaca cacagggctt gacctctaaa catataaaca tatacagaaa 43800 cgaggtcaga acatgttttg actgatgcca gtagtaacac agcagagcct attgctggtc 43860 actgttacca ataccttgtg taataaacct ttcatttaaa ttgagaggtt gtaagccccg 43920 aaaaagcaaa gggcttacag tacctcttgc ctgaacactc ctgtgtgtgc tttctaagaa 43980 atgcttttaa aataatgcct gtggcacaaa ttgatttgac actggctctc tttataagct 44040 gctatcaagg ttgtggggaa tagctaactc ttacccactt tccctgacaa ataggaaccc 44100 gtagttacct accaaaagta tgtaaaagct atatccgacc caaaggccag ttaggtcaaa 44160 acaccttgaa aggagctcag tttaaggaaa tcagtggtgt cacagtgccc cactagcgtg 44220 taaaagtttt catagtttga ctatcggatg tgcttagttt cacagctgag tcttaccttg 44280 tgatactttt agagcaaaag tcaaatcaaa gatgatttaa aaaaacattt caaagattca 44340 taaagaataa atgcctcctc aggaagtctt ctggagttct gcccacttcc cttaggtggc 44400 tctttactgt gcccatctca tagcctgtct ccttccactt ggtgtattgc agagtaaagc 44460 tcactgttta caggggtggt agaaagtgtg gtcctttccc agactccttt ttcccttcct 44520 cttctcattt ttcagaagat gtgtttgata ataaacgaaa caaaatgact aacacattga 44580 gctgagctac ataagcagat gtcagtttga cgtgaagagt ttaaaagatc tatgcattat 44640 ctggggactc ctcccccaga cctgaaggat caggtgctgc cttctatgcc acctgtgcag 44700 acagcaaaag aggaaaacca tacccacgtt cagtatgaac aaaggggaca tttgaactct 44760 gtgtggaccc ctcattggaa gggtgtttct tctcctgctg catccacaaa gagcactcct 44820 tagccttgcc ttttgtcagt tctctctcca ataaggcttg agcagagaca acccagtgca 44880 gttcagagag actgaagtct ggtgttccag gtctgagtcc tagctctagc tctctgtgta 44940 actttgggat gtcccaaagt aacttttcac aacttgatag gtgttaactt gaattttgga 45000 tacaggtgac tcttagccca tcccctctct gtgcttcaga tatgtcatca cttgggccat 45060 atgacctctg gacacctttc ctactttcca caatttcaga gcagcagagc agactggagc 45120 tcctgctgcc tctgagcttc agtgaattat cactcgttgg agggaagctt caagcatttt 45180 gttatctttc aagagcaaac acagtgtctg tcagcaagaa tatgtagcag atgctagtga 45240 acagcagtga ttagggttga atgctggatt taaatatgga gcttaggctg tgaaggaagc 45300 ctgaagaacc tagagcccca tgaagctgcc ctctgtgaga tctgacacca tttcccactg 45360 atgagccatg ggtctaatgg gtagcactga ttccacatac agtatgtgag tgcaatacag 45420 tgaaagcaaa gagaataaaa tgatggctaa catgatgttc caaactttaa acaggagaaa 45480 aacacacaat tccattatgt ataagaaccc acacagagat caggagaata acctcattgg 45540 agaatgaatg acctgtgtgg ggaatttagg gtagagttga gattgaaaaa atgggccgaa 45600 gtcaggtggc caagggcctt aataccttgt atacaagatg tgtagtcaag gaagaccatg 45660 ccttacttat gcatcaattc ccttgggcct acaaagagct gcctagcctg ggactgttgt 45720 agagaaaagc tacagtgttc caatgacaca gggactcctc catgtatgta tgagtgccca 45780 gctggctctg taataaatct tatttttatt tattaacttt tcttgcgcat tggcttgatg 45840 catcagttgg aagtcagagg ccaaacgaag tgaacactga gccaaaggaa gttctcagcc 45900 tttagggagg cagaattcac tttaaacaca ataaacaaat gaactcacat tatacaggag 45960 agagtcagaa gatcccagtg gctggtgtca tcgggccata tttgcccgaa gtgcctattc 46020 cttataggaa cccactccca gggttgatgg gctacatcct taggaggctt tatgcctatg 46080 ttctcctgac cactggctcc tccagggctg gcctttttta gtctctctgt agaggttcct 46140 gtagctggtt ggatataggc tttcacagaa gggtcagtgc cttgggtctg gttacaggac 46200 tgttaatctt gctttgttaa gagtaatgtt atttccccat ttccaaattc tccagggaga 46260 tggaatgtca aagatagtat gactgtagca cctaaatcct gggttccaga agcagagaag 46320 agaatacact gaagctgtag aaaggcctat tagtccatgt cagagattaa ctggatgcga 46380 ggaccatttc tgggatggtg tatacagaac tggagaactg gatagggagt cagaaacaaa 46440 gagctgaaga tgatgccttt gaagtttcca acgtggataa ctaggtcaac agaatattac 46500 tcaagaaagt attaacatag gattgagatg cagtcagtag taatggaatt gaaatttcaa 46560 agtatatacc tcatggatct cagggggtgt tgagctgatc acctgggcta acactcctat 46620 gaccctgggg aaaatcaaat gacctggtac tgtagccatg gtaggggtgt catcacctta 46680 atccaactgg gacagtgctg tttgatattc atctggaact tggtgcagac ccacattttg 46740 ctgggtttca ccacaaccaa ggcttttttg attcttttct cttttaacat cagtacatca 46800 ctgcaaagtt aatcctcata taataggaga tgaaactaat tgcttataaa aacaagattt 46860 ttacaacact aaaattgttc aagcatatgg gcatatttat agttgcaggc agtgtttcag 46920 atgcagactg ttcttggctg cagtggttgt ttacaggcag catctgttct gattaaatat 46980 ttgatgatta tccccgaatg ttttaaagca tagtactggg ctctgctgac tgtacaacaa 47040 actggcattt ttgacctata gggcactggg ctaggagata cagttctgag ggaagtgaaa 47100 gatagttaac aactgcacaa ctgacccttt attagttgca ataaagcaat ccaaccaccc 47160 aacccactgt gatggctttc ctactattta aggttggtgg tgtcaaagag acaccctcct 47220 gtacagtgtg cagtgaatca acatcatttc cacaaaacct ccttcctgca caaaggaatt 47280 atcatacttt gttacgaagt aaaattttcc tgtatcagtc acaggagttc accagttaag 47340 atactgttag ttgaagactt ctggggtgac ttaatgaaat agctcagcca tctggtttaa 47400 aaactggatt cttctatccc tccacacagc tgtccatgca cctgcatcat ctcaaggctg 47460 gtctccctgg tggtagaaag gctgacagta aaaactggag ccacatgatt ccttgcttag 47520 gcagtgtttc ttcatactct cacatgagag caggcatgtt ctttccctag gctcacagta 47580 aacactctgt caaatctcac aggcccaaag tgcttttggt tatccccatt ccaagccaat 47640 ctgtggcatg gaagatagca ttaccctgac tgccttagac taatatacct actccacttc 47700 tggggctggg aataattttg aggtcaacca tccaaactgc atgacagcca ttccatggaa 47760 gaggtatggc ctaaatcttt ggggcaacct gaattcatga aaactctctt agatttatgt 47820 aactattttt agaattcact tctgtatcat ttaattttac taataaaaat accaccttta 47880 ccctaaatgt cagccaagcg taaggctccg ttgggacaga aggaactatc aaagctttgt 47940 gtttttatac attagcagca tttgacaaag aaataactct gaaggaagga gaataaccag 48000 gcagagtcta gatgcatgga aaagaagtct ttgagaaggc ttcgcaggct gaaggaaagg 48060 gcaggactac ttcaggaata caacgtttaa gtaaaagagg ttggggtctg ttgatcttga 48120 ggagagatga ggatggactg gaaaatagga gtgagatata gtaggagagg aaaggatatg 48180 gatgatgtat atactgtatg ggtaaccatc agtcgaccct aagaagataa tagttgttaa 48240 atggttagct atttaatgaa agaaacctga acaagtaata atcttgagtt gcaaagtggc 48300 tggagtcaca caacagacta aatttctggt agaacaaatc cagcagctta tgtgaaggtt 48360 accatgtctg aagctggata gaaaaggtct aacttccaac caaagtcaca gttcttgagc 48420 tcggtacaca gagacagact gctaacagct gatgtgtcct cagcgagagt gtcctcattt 48480 atatcctcgt tctcttctgc ctcctttttt tgttttaaac ttttgggaag tctcatcatt 48540 caatacagtt ctaatatatc acaataacag aggcggccca atttctacaa attgactaat 48600 tctatccctg aaaagttcat acaataaaac tatacaaagc atcattttca accatcctat 48660 agaaaaattt ccctattaaa ttttaactct aaatcctcta tctctgttaa taaccttact 48720 aaaaacttcc ccatcactgc ctgccaggga gatcaaaaga aaccaaattt aagaaacctc 48780 caacacctgt acctgactga aaagcaaaca tacagacctt tcagtcctgc ccctactatt 48840 cagctcctat cacagagaca tggtggatgt ccccttggga agcggatagc tcttaggtgg 48900 aagctaggcc tgcaataagc aggccaggaa acatgtctcc caggccccat actcttggca 48960 gaagcacttg gccaccagac agcatgtcct gtcaacctac agagttctta aaaacaaaca 49020 ctgggaccca gaatagtacc ctgtggtcat agtgcccaca gttcactaag caccctcaca 49080 ggtctttgac agaacactga ctgccaggtc acctggtggg cagagaaatg gaagattccc 49140 aggcccaact agcatctcag ggaagaacca caagcagagc aactttcaga gctggtcggc 49200 cagcgttggc acccagggaa gcaagtgcta ttccatattt ggagagaaca taaaactcaa 49260 ggaaacagag aagtcctact caataccgtt ctcaactgaa aacaagagaa cttgcaaaaa 49320 agaaacccag ttttctggag tccatggaga aatatgaagc caatgctcgg ctaacagagc 49380 agaaagcctt ttataaataa tgccagtcaa agctccaaag gtcagagctg atgcatgccg 49440 gattgttctg acaatttctt aggtttctag gcaacaagga gctggtcaaa cagctcacct 49500 ccaaggacat actttataat accaccctgg tagacgagag cgaggcagca gtgaaggcaa 49560 tagtcaagaa caggagaggg aggtaaagaa caagatgctc ttcagacagt ctggacaaag 49620 acagtcccta cccagctctc aggagttgcc tccttaagaa ggtggaggcc caggcagctc 49680 ccagggtgac cctaaagaca gactccaagg aaaagggtgt gagggcaatg gtgaatataa 49740 ggaggtcccc tttcagtagg cagagcaagt cagttcaggt cttattttta gagtctctga 49800 acagtgaaga gaagctttct gtggacagca ttccaccacc atgggagggg aaaggtgcca 49860 tgagagactt ctccagtggg gcatacaagc attgtgcagt gatccccaag atccagccac 49920 tggcaggaaa tcgaaaggca agcttcttaa atacatagta tatggagaca gaagtgtgga 49980 gcactcccaa aatgaaaggc caagacccag gaacaacctc cacaacctgg agtatataca 50040 aatgaaccca gccctgctga ctcagatcca caccatccta aagcaggggt ttctcatgaa 50100 tgaaagggct aagtatttgg tggagagaat gagaagtctc ccactgccca cacatttttt 50160 cttcagagat ttcttttcca agagcccctt gaataaagga agggagggag cactgaatgc 50220 cccagaaatc agaatgcatg gtgcgggaag acgacaggaa atagttctca aagagatcag 50280 aaaataaatt ggaagcaatt tcattaccac aaagaacaga cattttttct aaggcacccc 50340 tcccctttcc acccaattgt cattcagcaa ctactgaata cttaccaatg aaaaacgtta 50400 cccctgacct caaggctgct cctgagctct ggtagaaaat gctttccttg tctataaaac 50460 atggcaagca aggcaggatt taacagtaag ggcacagtag cactgcaagc cttcaaatgg 50520 aaacctggag acaagcagtg agaacaggaa gcaaaagcag ggcaggtgaa gctaggacca 50580 gggcatctgg aactttccac acaggttgga tctccatgcc agacaacagt tttcaaggaa 50640 aaatatctaa gaggaacatg actttgggaa actttttggc agtactgctt actgtatact 50700 agagagtaaa agaatttggg gaacattcac caatttgctt cttcaggggc ttgggtaggg 50760 aacgtgaaca ggaacctggc tctaatttct gaactttttt atcagtaaaa acaatccaac 50820 aaacgaaagc tagtcagtga gagaactggg agggtctgcc ctccttccct gagtcaagcc 50880 ttctgggggg acctcctgac atttaattaa gcaaagacaa cgcccactga aggaagctga 50940 cctgaaagtg acacgctact gtgaaatgag catgaagtgg gagcttgtta catatatgaa 51000 atggccagcg atcctgagca aagcgcttca gagcttgaga cctaagtctt ctcatctata 51060 tactgagggc tggacaagat gatctgtcaa gccattttta tccctaatcc accaaaatcc 51120 aatgctttag tttattgtca caaaagcagg tatcgaatgg ctatcctgca gtgcctccaa 51180 tcaacattca gactttttcc ctgaggcaat ataagataac agttaacatg tttttatcaa 51240 ttaggtggtc atgagataaa tatatatggg aagtggtagt ttttcactta aatgcatata 51300 ataatggtac agctctcttt gaatagtatt tgtttatttc ttaaatattt aagttcctaa 51360 agacggtaag aataacccaa ggaagtgaaa tcaatgtcac aaagcacatg gctaaataac 51420 tgcaggtttg cagtgccatg tgtgagatca gatgacagaa gggagaacta cctttaggca 51480 gaggcttctc atgtcccctg gagtggccat gtgctgttct acatgactac ttccacttcg 51540 gttatgtaga agctatttaa agcacacaga tgtttgtgat gagaaaaaag ccacccttaa 51600 ttgaataatg gaaattataa gcatgatttg agggtggggg tggaggtggg agtagagatg 51660 ggtagaaagg agtgcaatgg aaacaaagga gccttcataa aattcaagtc acttcttagg 51720 ataacgtgat tgatttactc accaccttct taggaacata aagcaaacaa gtgggttttc 51780 cttttactgc ttttctgaaa tgagctacac tcaagaaagc agcacggggg ttgtgctgtc 51840 cctgcacagt ggcaggagag tatgaggagc aggtgaatgc cacaacagct ccatccaaga 51900 tcatttttca catgcaggaa ccattcttat actacccttt actggtaatt tctgtagaaa 51960 tctggaagtc tggttgacac cctcctgtac agtgtgcagt gaatcaacat catttccctt 52020 ggactttgca atcacggtgg cattcataca ttcattcaac aagtatgtat gtacaggaca 52080 gtggagtaaa gaaaacagat agttcttact ctcacgaggc ttaaaatttc aggagggaac 52140 taggcagtca tgaagtaaac ataaaaacac agattgtaat aggcactaga gaataatgaa 52200 gactttgggg aacacaattt aaattggaaa aatatctcag ttccgttaac acatgttgaa 52260 ggggaatagc attgttttgc tggatttggg gcctggatgc aagcatgttg ggtatgcatt 52320 gtagggtaat gcatttcctt ccatttgggc ccaagtgtat atttaccacc cagttgtgat 52380 gagctgggat cctcctgctc aatctcagct tgaagcactt ggaggttatc tgcctgctgt 52440 gggtgattat tttggagcaa ggtacttcat ttgcctcaag aaacagattt gataccacta 52500 ctgtgccctt ttggaacaga gaagtaggca agaccccagt gtgaggcaga gtgatgggat 52560 ctttagggac ataattgatg atgtaactga tgatgatttt ggagtttata catttccaaa 52620 gtttcaaaat attttcactt ggttgattta tctttatggt gatgacacta cgtagatata 52680 tgcccttctt aaaagttaca gtaagaggct gggagcggtg gctcacgcct ataatcccag 52740 cactttggaa ggccgaggtg ggcagatcat gaggtcagga gattgagacc attctggcta 52800 acacggtgaa actccgtctc tactaaaaat acaaaaaaat tagccgggcg tggtggcggg 52860 cgcctgtagt cccagctact caggaagctg aggcaggaga atggcgtgaa cccgggaggc 52920 ggagcttgca gtgagctgag attccgccac tgcactccag ccagggcaat gagcgagact 52980 ccgtctcaaa aaaaaaaaaa aaaaaaaaaa aaaagttaca gtgagagttg acattgagaa 53040 aagggaggcc cagccagggt tatgcaaaga cacagtaggg aggaggatgg gaagtttctg 53100 agacacccca gtaactgcat gggtccacaa agcacatgta cagtctgctc tatgcactgc 53160 aggtacagcc acgaataaga caaagtctct gccctcatgg agcttggtgt ctgtctactg 53220 gagcagacaa aaacaaacct gctttttctc atttgcctct actgtgggtt ccgtgtataa 53280 ctctcaaatg ctagcatttc catgcattcc atccttgtcc ttctctcctc tctgcctttt 53340 ccaggagaat tttcctagcc acaggttcag ctatggtcta tgtgctggag tcatacattt 53400 ttatcttctg tgtacgtttt tctctagacc catattttta attgccttag gacagctctc 53460 cctggatatc cctcagacac aactaaaaca tcattcaatt gtactattaa taattttccc 53520 ttcaaaatcc actcctcttc tctatagacc taacagcaac actgtccgtc cagctctcaa 53580 aacctgaaat gtgggagttg tctttgactc ttatctttcc catgcatgag cactgaatca 53640 atcagagtcc ctagcatgtc ttggactgtg gcctcccttc tatcttcaga ttatctgcct 53700 ttttagaatt atggcaataa cttaactgca aagaccacat gtgcacttgt gctctttcag 53760 tttgtaataa atataaaatg aaaagtgatt atgtctttgc ttaacgtctg caaaataaaa 53820 gtccaaagtc cttggtatgg tctataaggc cctcattatc tgacctgcct gccttcccaa 53880 tctcatctta atcccttaca gcctgacact cagacatact agactttcca cctaactcac 53940 tcacatacac ctatcctgta tgtcaagatt cggcttgacc ttcatcacct acctatctgc 54000 agtatttttg gatctgaatt ctctgcccac attgtacttt cacatacttc ttttaccctt 54060 agtggtttgt acttatgcct ggtctaacta gattgtctcc ctgtaacaga cttcttgatt 54120 caacaaagca gctctgaatc agcctgaaac ctatggcaca ctgcaaaatg gcaaacattc 54180 aataggtatt tgcccagtaa atgttaatga aaggaaaaaa attcaaactt cagttggaat 54240 aggattagag acaagttaaa aaaaagtttc ccatagaaat cttcctcatc gtaaatatca 54300 tcatcctaaa tgtcccgagt ctttccatgg gtctaattta ccaaatcatg aagactctct 54360 ttctcactgt gtatgtgtag tgggagaggc agagacagaa cggttttttt ttttttttgc 54420 aagtctgctc tctggattcg tttttctggg gatgaaatct caggctatgt agcttttctg 54480 gtcccttttt ggtaatcaac aaatcatcag tttctctagg tattaaaaag cctacacttt 54540 tgaaacacca agaggccaaa ctctctctta attgaaaaca taattctgcc tcttactgag 54600 gtctttgggt gggaagctta aagacagcag tgttggggca attggttttt cttttcctcc 54660 ctccaccttc tttcccattc aagagctgtt gctgcccttt ctggagggga gggaattaga 54720 aaaaaagatc ctgccttacc cagtcactgt taattattac tttgagccag ggtggggaat 54780 gactttcttt cctggaatac accctgctgg aaaccacagc tgagattctc taagctggca 54840 gcttccaacc tctcctccct caacagcttc aacattatat ggcactcagc tgcagggtgc 54900 ctggctccag gccggcagtc catttgtgca gggtagtttt caagatggct catagcccat 54960 ctctttcagt gaccagcgtg gcctatggga aacatacatc ttgactccat tattggtagg 55020 agtactcttt agttaactgc cacaggccag ttcagacacg tcttaccctg agagcctttt 55080 cagagtcagg taccatccct gtgtccccca gcatctgaag atcacaggtg aaggtctcca 55140 agtagttcac ttaaaaaata cctcagtagg tttaagaaca gggaaagctc ccaattcatt 55200 ctgtcaggag tatgactctc atccccaaac tggacagata tataatatga aaactacaga 55260 ccaatattcc ttatgaatat agatgcaaac attctaaaca aaatactagc aaaccaaatc 55320 cagcagcata gaacaaggtt tatgtagcat ggacaactga gattatccca ggaatgcaaa 55380 gttaattcaa tatacaaaag tccattaata caacatatta ataaaggaca aaacaacatg 55440 aaaatcttga tacagaagaa gcatttaaca aaacccacag cccctccttt tttttttttt 55500 gattaaaaaa cactcagtaa actaggttta ataaaagaat ttcctcaact tgaagcaaac 55560 ccacagctag ctaacatcat actcaatggt gaaagactga atgctttccc cttaaaatca 55620 ggaacaagaa aaagatgtct gctcttgtca cttctatcca atattgtact ggaggtgcta 55680 gccagcacac taaggcaaga aaatgaaata ataggaatct agactggaaa ggaagaagta 55740 aaagtatttc tgttcacaga tgcatgatct catatgcaaa aaatactaag tgacaaaaaa 55800 agaattttag aaaagctaca atatacaaaa tcaatataca aaaattaatt ttatttctaa 55860 caccagtgat gaatacaaaa ataaaaatta gaaaataatc atataattaa agtggcatca 55920 gtaaaatact tagaaaaaaa ttaaagacgt caagacttgc acactgaaat ctctaaaaca 55980 tcactgaaat aaagacctaa gcaaatgcaa agacatccca cagtcatgga acagaaaacc 56040 taacaccatt aaaatagcag ttatttctca aatttatcta ccaattcaac taaatcccta 56100 tcaagatccc agctgttttg caggaattga cacaatgatc atataaaaat tcatatgcaa 56160 tgcaagggac ccaaaacaga caaaatgatt ttggggaaaa aaaaaaaaaa aatggaggac 56220 ttgcacatcc caaatctaaa cttactacca agctacagcc atcaagacag tgcggtgctg 56280 gtataacgac agacatatag ggcaatggag taagactgag aatccagaaa gtcttatatt 56340 tatggtcaac tgttctttga caagggtacc aggaccattc atggggaaat aatagtcttt 56400 tcaacaactg gtgcttgggc agatggatat acagatacca atgcacttat gcaaaaaatg 56460 gatgaaatag gaaacttcac tacattctac tgcatgctcg gtcattttca atcatttagg 56520 tggcaacact gacaagataa cagaaagatg gaggtaataa catgtgaaag gcaaaatggt 56580 ttgttttttt ttttaaaaat gacagtctct atcatgaatt tacttacact ccaggcaaag 56640 gttattagaa gaaaaaaaga tgtaagaaaa ttccttaact gaaatgtgga aagagtatca 56700 agaggagacc ctaagacact ctgtaagaat cccagtgact cctcactgtt caactaagaa 56760 atgtacccca ttatgctgtg ctaccacgga agcattggag gcactttggg ggttgatgaa 56820 gtcttcatgg atgaggtact ttaaatatct ggtcatgaag agtatttgag aaatatgaca 56880 agtgaagatg ctgggtagga atgcagcgag gaaagtgtgt aacacaaggc caaattggaa 56940 aggtcagtga gggggcaatc tgtggaggca ctgaatgcag aggatattaa aattagcaag 57000 atagtgttct agcacaatga aaaggattgg aagagggaga tgagagtcag ggagtgaaat 57060 taggcagctg ctaagaatgt ccgggtgagt cagaggatca ggacctgtaa gggcagtata 57120 aagaaggaag gaatgatggg agaggtttag ggggaaagaa gtgacaacct gtgacaattg 57180 aggaatgaga gattttgatg attggggtga aggttacatt tcttaaaaag aaacaaagaa 57240 tggtcggtcg atagagatgc aagatgaaga attttgtttt taggactact gactatgagg 57300 taacaaagaa atcccagaga cagaggtctg agcaaaagat atgggattgg ggaagaatct 57360 ttgggagtga ctgaggttga ctagagggaa ctgggcaaga acaggtaagg actttaagca 57420 gaattggagg agtatccatc taaaatctgg gtaaactggg atggaaaaac aagtagccag 57480 agaagcaaca gcccaagcta gggtgttgtc aaggttatag atgttactga ttttggcaat 57540 gaggagatta taaggatcct tgaagactgt actttcggtg aaactaccat gcattagtag 57600 cctttcacag tgatatctac cccacacctg catcaaaatc ttgcagtgcc tattaataaa 57660 tgccaaccca ctaacgggga ggggagaaaa gacttgggac tctgtacttg taaaaccctc 57720 taccctcccc aggcaattct ttacacacta acactgttga ggtaaaagga gacaagtgag 57780 ggagcaaatg gaaggtgtgt ttttggatta tacagtggct catggaaggg tgggaggggt 57840 acagatggcc cttagacact ggcggaaagt cagagaaaaa aaattacagt aagcaggtaa 57900 agggatcaag actacacagg gactagtctt gggacgacat ttcttcctct gacagtttgt 57960 atggaattct tgagaaaaat tcctcgaagg ggcctgaaat ctcagaatgg tcatgttttt 58020 aatgggaata gggagtgatg ctgccccatt acaaccatct gttctaacag aatgtctgta 58080 ccgaggaggg atgagtaaca tcggcaagtt ctgttcgaag cctttttcaa gtttcttttt 58140 gatatgtatc tatctatcta tcatctccct atacaagcaa gcatccccaa aagtagttgt 58200 ctcaggaaac cagggttagg atgaccagct catttgctgg agctgccaag gtccagaaaa 58260 gtttggctgc aggctgtttt catgttttat gtatgtttga aatgttctat aataataaaa 58320 ggttaaaaaa gtttacattt atttggaaaa ccagttactt tagtttatgg ttcctttttt 58380 tccctccaga gcttcctgga gattgaggtc taattcaaag aaaaccaaaa tatataatag 58440 agtacctggg caaaaaaagt acttttataa cataacattt ggggtagagg aagtatccac 58500 tgtagtcaaa atgtctatgt tttgctcttc cttattgttc agggacattc cattaaatag 58560 taatgaaaag gcagcaaaag taagaggagt gacaacatgc ccggcataat taagcaagct 58620 agagcagcta ttctgtgcaa ccgacgattt tttttctcta aaattttaag ggtaggttca 58680 ttctgactct gttaaaagtc tacttgatgt gaacaactct atatctgata acctatttca 58740 attaccactt taaaacttgt catatggata cgttattaca attgtagaac tttaataaat 58800 accataataa taaaacttga gaactgaaga gcacacattt cttcacgaat ttattatata 58860 aaacgccctc agagtattta atttctcctc actttaatta cacattaaga agcacagtgg 58920 atgagaagcc tttaagatga ctacagttgc acgaaggtcc ctttcatcaa ggtagcgtat 58980 gtaccctaac agtgttctaa aggctggccc agaaaaaccc catgttacct tatcacaata 59040 tggaaagcat tgtcttcttt ttccactaaa ttaaattatg gtgaaaagtg ccacagtttt 59100 atttagcatt atggtacata acaaacagtt ctgtctcaat tatgaaaaaa attaattaaa 59160 ataatcctga aagacatcct ttttctcccc ccaatgattt gaaagctgca tttttcctgc 59220 caatttcaaa caaacaaatc atcaggttga tctacagtaa tcagttaaaa caatcagtca 59280 atcaatcaat caatcaccaa ggcacaagct cagcacatta gctatagctt gtagcaaaag 59340 gatatatcaa tgtctcacct tagttaaaaa tacataatcc ttttatttta taatgcaata 59400 aaagaaatta acaacatcac atacacagaa gactaggaaa ggggaaacta cttacttctg 59460 gaaatcagta atgtaaacct acttgtactt ttccatagta catgaaagta acgtttaaca 59520 tgttttgaat taattaatta aatttaatct gtggggctat acaatgtaat tcttaggagt 59580 aatagtttca ttcatttcca ggtcagctta ctgtatgatt aagtaacaca aggcacagta 59640 gccatctttt tcattatgtt gcaacactga tcacgtgcct cgataaaatg gctgattcaa 59700 caagatgatg gcaacacgaa ggggagactt tggattgtct atttaaaatc taggtaataa 59760 gtaagtaatt aataaaaact ctatcttaag tgcactttca catgcttttt gtttataata 59820 aacaaacaac aaacttccta actttgttgc aataggcttg actaccattt catttggcca 59880 aatgcacttt ccccagtaaa cttaaaacaa caacgagaac aacaagaaca aaaatccctg 59940 tcctttcata tactaagaaa gaggattggc tactgaaaca gttcattgca agacacatga 60000 agacgacata ctgtggcatg agttgttttt gtttttaatt tgttgtgctg ttactaaagt 60060 tctgagggct gcagttaaaa cattccaatt tctcccttcc ttccatcttt ctttattgat 60120 tgattctcaa gattttgcac agaaaactct ttgggggcta gaacagcagt aattgcatca 60180 cactgttttc aagacttcaa gtttcaaaag caaatcatta aaaaaaatac agttcctgat 60240 ttgagttaga tacagggaca aaaaagtagc acatacttga aggttacgtg gtctacaaat 60300 ggtggcaata ttttccttgg gagagtagtt ctgttggtat atatttttta aatactcaaa 60360 aggctcaacc tcaagcagta ataaacacaa gcaaaagtga tttaaccctt aaaataaata 60420 ttcagaaaaa cctctctgta catacaagtg aaagaatatg taacactttc acgcaaaaaa 60480 ataattataa taataataaa ggatttgttc atatatgtag ctgaaatctg ctgttccagc 60540 ccacatgtcc ccaataaaga agggaggcac agacataggt gactactgtg gttgactatc 60600 ttacagcctt tttgtactgg gacactatca ccaccaaaaa tttatccctc gttatatttt 60660 taaaattttt taaatttttt cttttttttt ccttcctttt ttttgtttta ttttgttttg 60720 ttttgtttta cagcatgcca aatcctttgg catacgtgat ggccttcaac aatctctctt 60780 taagtttttc tttgcttgag tattccggaa gtaaaagcac attaaagcaa gtatgagatg 60840 taggtaacct aaatagagaa aaggggaaaa aaacaggaaa actgtaagtc atgggaaata 60900 cacttagaat taaatgctcc tatttttaga ttgtatatag ttgagacggt ctgcaatgca 60960 aactatacat taatgcaaat cataaacttt ttgttgtgta actaccaagt tgcctttatc 61020 ctataaatta ctcaaagcta gtgacgatga taagatactg tatccattga gtttttacta 61080 cataacagat accattttag gtactgaatt cttacagttc atttaactaa atctttccac 61140 aacaaaacca cagagaggac atcagtaaat gcactttaga ggttaggtca ctgagaagtc 61200 aagtaacttc ctctaaggtg gagaaaatac tcaaacctgt tttacaagac tgcaaagtgt 61260 gtgctcttaa atgcttatta gaaacactgc tggcaatatg actaagaaaa tgatttgata 61320 acaggattct agcacaatca aatgataatc ttccgagcct caatgtaacc attctaaata 61380 gatgatcatg ttatatggct ttcaattaac aagctgggaa tcaaaaaagt aaatgaatca 61440 cactaatttg attccaaacc aatgtgagcc ccataataat ttttaactag ggcaatttct 61500 taaaagtttc ctcacacaat gacagcaaag tattttctca attgtctaat atgatttggg 61560 gatttgtata taaaatcacg aatgtgctca gaaactataa agacagttca tatgtatgtg 61620 acgaggaatg caaggttttc ggtaggtata cagtcacaag ttaataatta cctacctttc 61680 tgtgtctggg ccatttttgg ctataatcat ctttaatttt cctagtcctc ccacaggtgc 61740 tctgtctgtg cccgttgtaa actgcaagaa gagtcttttc tgttcatctg taaatgaatg 61800 aacgatttcc cagaactccc taatgagaaa aaatacaata ctggtttcag tttggcattc 61860 attatgactg gtactaacat aagcttatga tttgcattaa aactatatta agagacaact 61920 tggaagttaa ttatcaggat agtatcactt ctggtgattt aaaaatttcc aagcaaattt 61980 atcctgaaca gctctgaata cgtaaaaatt tagattagat tacaatatag taaaatatta 62040 gtactacaat agtaaaaaat tgagaaaacc caagtgtgta gtaacaggaa gtgactattt 62100 aaactatggt ataatcacat tatgcagtca gtaatgagca aaagacaaaa tcctatgaat 62160 tgaaaaagac tgaaatgaat atttggaaaa attaactcca ggtgcctttg ggtatatatt 62220 ttatttatcc tttctccttt attctcctgg tctactcatc ctttaactca actttgggag 62280 gaaaaagtga tacagattaa ggacaaaaga aaaaaagacc ccctgcccca accaactggc 62340 cccaaatgca aacaactaca tacctaatag cagtaataca aaagttcaat ttttatatga 62400 actagaatac tttaaacaag taatatgtgc tgtgtatgga ggaggagaat tattctgaca 62460 tttctgccac ctgcagttat tttaagagaa tgatttatcc tgtggcattc ctaaaatcta 62520 tgtaataaaa gctatgtttt aatgacactt atgttagttt gagttctaaa aaacgaaata 62580 caagctcata aagtgcaatc ttgaagttta tttgaataat caggcatcta taaaacatat 62640 atacactagt tcatagctaa ataaattttt ttttttttga gacagagtct tgctctgtcg 62700 ctcaggctgg agtgcagtgg cgcgatctcg gctcattgca agctccgcct cctgggttcg 62760 cgccattgtc ctgcctcagc ctcccaagtg gctgggacta taggtgcctg ccaccacgcc 62820 tggctaattt tctgtacgtt taagtagagg caggatttca ccatgttagc caggatgggt 62880 ctcgatctcc tgacctcgtg atccgcccac cttggcctcc caaagtgctg ggattgcagg 62940 catgagccac cgcgcctggc ctatagctaa ataatgttaa gattaaaaaa ttaaaaaaaa 63000 aattaaaagt atttttagtt gcttatataa tataaaatgc attttaatag ttatttagaa 63060 agttctttcc agagccaggt gtggtggctc atgcctgtaa tcccagcact ttgggaggct 63120 gaggccagtg gatcacctga ggtcaggggt tcaagatcag cctgaccaac gtggtgaaac 63180 cctgtctcta ctaaaataca aaaattagcc gggcgtggtg gcagatgcct gtaatctcag 63240 ctacttggga ggccaaggca gaagaattgc ttgaacatgg gaggcggagg ctgcaatgag 63300 ctgagatcac accattgcac tctagcctgg gaaacatttt gagccatctc aaaaaaaaaa 63360 aaaaatttca tctcaaaaaa aaaaaaaaaa aaaattccag aatgttagca gagaacatca 63420 cacatcccaa accagtaatt acaattttct accttttgat attctaatat cccaacatac 63480 tatttttatt accaaaatgc tggcattttt ggtgctgcaa caccatttat ctgaaataac 63540 ttaaaagttt tattagaatt cttggctttc tccaatctct tgccacttcc cttccctgcc 63600 cctttacaaa tccaccagtc agcaagagaa aacaaaaaag aaacacacaa caacagaaaa 63660 ctggacatga aacttgcagg agcatctctc aggtaaggag gagaggaatc ggaccccagt 63720 tcatgatact ccttttgggg aggctgacaa gagaaaacaa gtctgctgta gcacagaacc 63780 ctccaacata gcagaaaagc tgccctgcag tgggtggtaa taaagcctcc tcacactgca 63840 ggagggctct gaagcttaac tgaaccagct acacctaagg aggtagacca aagagcacca 63900 ccgaagaaca gagacagacc ctgcaggaag tggcagatca gcagtggtca caatgaccag 63960 tctggctata ttattacgga gctgtttctt tggactttta aacgaaacct ttaaaaattt 64020 tatacaatga aaacagggaa caaaatgcat ctctattcct ataagtgtta tgtgtgttac 64080 attaacattt tgaattaaac aagaatgcat atatttagaa agctgaagaa aacacgaaga 64140 agcttccagg tttccacata aaagtggtgg ctgtatcgat cacatcctac tcacatctct 64200 aaaaatctac ccggatcaaa aaggggaaaa taaaaaaaaa acctatgact taggtctaga 64260 gtaaaactag gagacagaac aataaactcc aaataccaaa gaagtgggga aatgagcagg 64320 gtccagcagg agctacatcg aagagtggct tgtgcggaat catactgatt agggatcacc 64380 caaggccaga ccccaccccc tccaccacct gcccctcaac agagcactac tgagtgtagg 64440 ttagagcact ggcaacaggg tggttaaagg aaggactaca gaaaagtact tgggtccagc 64500 aatggcaggc tcaggaaggc accatgcatg aaaggaaggg gggtaccttc aaaagcagaa 64560 gtgtccctta agcggctgta aaggggtgga agcagctaat gaaaaagagt cttcattaag 64620 ctacatggag ctgaaaaatc agaaagtggt gattctgccc ttactaaagc aacagaagag 64680 ggatcccttc aaccaagacc cctaaagcca cacaattcct ccctgctcca ccatgaggtc 64740 tagtaataac aggtccagaa aaaagtaaca tctgttatag aaacataaac aagaaaaaca 64800 gaattcggaa gtctaaataa agttattatg ggaagagtct ggcgaatgag aagcaaaact 64860 ttccggtaga caaaagtaga ccagaaaaat tcagtcataa acaatgggaa actagtaaca 64920 ccacattcca acacaaaagg agaatgcagc agcagacaag acagaccacc agtgatgaga 64980 aatacaaatt cagaaagaaa tgagcacatc ttaaataaaa ataagaatac taaaaaatac 65040 tgaagaaata tgcaaggtaa ctttggaaat aaaggctaat tttattataa ggtgaccaaa 65100 gaagaagcag tatgactaaa atttctactg aggacagact ctagaaaatt aaaaaacaaa 65160 gaaaatgaat aaaataaaca taactaaaga aatgcatatc aaagcataat aacgaaaaag 65220 attaatagct aactacataa acataaaacc tttcatttgg caaaaaaatc ctataagcaa 65280 ggttaaaaga caaatgacaa actgggaaaa aatatttgcg aatttaccag cgttaaagga 65340 ctaatctcct taacatataa agtttctaaa agtgaagaaa acgaccagct gagcagcaaa 65400 atgagcaaaa gactatataa aactataaac agctctacaa gaaaaaatgt ccattatcat 65460 tcataattga ggtaagctca aaaattgtaa ctatagtaaa ataccatttc tcaattggca 65520 aataagtaaa catccacatt taacaacaca ttctgtttgg aaagttttaa gaaaagagat 65580 actgttgtaa actgctggtg ggaatgcaaa atgttatttt tctgtgaagg aggatttggc 65640 agtatctagc aaaattacac atgcatctac catttgatgc aacaatccca cttctaacaa 65700 tttatcttaa tgatacttta catatgtacg gaataatgca tgaacattaa gaggattcac 65760 tgtgacatta gtactaacag caaaaggtta aaaataacct cgatgcccat aaatattgat 65820 aagctatgct gcatccacac aaaggagcag tattcagtca tacaaaacaa aatggaaaac 65880 acctctgcaa taatgtggga tgattctcag gatacactag gaagattatt ttcctagttc 65940 tgtcctctga taaggcctac aagcagtaac gttcaaaagc aaaggccata ctttgcatct 66000 aaaatctgac ttctaaatgc cattctccaa caatttattg gaaaaataac ttattccagg 66060 cctgagaatg aatgttcgag attagttaga aatctcaaaa tctaataggg tcattttaaa 66120 agcacacgat agctaagcaa tttgaatatc atttagagta atgactgtga aacgtattaa 66180 atacaaaaac attcattagt tcgtaatatt caaaaaggca gcaaaaacca accaaaaaac 66240 aaaattaaat tgtcactatt aaaattatta cattaactcc ttactctaaa aaccttaaat 66300 ctattttatc atgccttttc tgtagaactg tttttcaagg taatcaaatg gcacccaatg 66360 atgagaaaaa agaatgccag gtatatatgt aggacaagca gatggaaatt ttttttcccc 66420 aaacagccat tttgcaatcc ccaatgagat aacagattaa ggtaatgata ctgataaata 66480 cgaaaatcag gtgaagggca ggtagcaggt tctggaaaga tgatgatggc aacgacatag 66540 ttattattat tattattttt tgttttattc cctcccaacc tcccctacaa aaacagcaaa 66600 ctgaatgaga aaaccaaaga cccagagaca ttatctacaa caaaaccatg aaccattgca 66660 tataattgga cagaaacaaa gctctgacaa ctacaagact ggttagtaag gaagcagatg 66720 caaggtaact gactgggttt ctgacagccc tgagaacact gccaacccac tggaaagcac 66780 aggccaatct gaaaacaggg cttaaagttt taaaaagttc tacaggatct aatttgcaga 66840 tgattacaaa gggatcatga tgtagtaagc tctgggccct taaaacaccc gaataccaaa 66900 cccccaccag aaacaaacct tgtaccgagg aaaaacttct gggaataact tccgaatgga 66960 ccaggtcagt aataaaaacc aaaaaaaagt tcaaatatat gtgtgggata gaggagtaaa 67020 gaaggcagtt tcagaaagca caagggcata tttttgacca ttttacaaaa acacagactt 67080 ctcctcgtcc ctaaaaagcg aaaaaagtta tcctggccca tctctccctc gtccaagtat 67140 gagaaactca tttcactcac acacacacac acacacacac aaataaataa ataacagaac 67200 agagtgaaac agtgtaatta ttagagaaaa agtatgtgca tatacatgag aatggtgtcc 67260 ctacagaaaa tcaaagtaca tgaaacaata tgcaaataaa acatgaaaac tgtaaacaaa 67320 tttcaaactg agctaaaaag aatttaaaaa ataacaaatc attagaaatg ggaaatttct 67380 gaatgagggt aactgaaaaa aaggaagaca tgacacaact aaggagtaat tagaaatgca 67440 aggaaaaaaa tcccatcaaa tacaaagaaa ctaaaactaa actagaagaa acataaaggt 67500 gaataaaaca gaacaataat accagaacct gaaggcagaa gaaaaatctt aaaatcaaaa 67560 agaaacaaac ccatgcttga gactctcctt gctggtccag agccacagtg ctgctgtgta 67620 ctggcaggag gaattctgct ataattggtc ctggcagtgt tcacctttcc tgcaagtgtt 67680 ccacagccca gggacacaat gtggtcagga gcactgccag gaacaccagc aagggggagc 67740 ctgccacaac aggcacaagg ctcaggaagc actctccagc ccacgaaaat ctagtggggg 67800 tcctcttccc tcacccaaac acactctgcg cagctcagcc tggagaaggc ccctcaagca 67860 gcactactag gaaccagtgc gagccccagt ggactgagat aaaagcaaca aaccaaaaca 67920 gcaccataaa gcctctgaaa aatggtcact ggaaccacag ctcacaaata tatgctagta 67980 cctacatgct ataccttaac aggttactac tgaagttaaa atttttaaaa agtacagagt 68040 ctcctgatat aataactaaa atgtccgaga cacaatccaa aaattatctg tcataccaag 68100 aaccaggaaa attacatgaa ggaaagaaaa cgccaacact gggatgagta agatgctgaa 68160 attatctggc aaggatctta atgctgccat cagagaaatg atttgacaag caattacaag 68220 ttctactgtt tcaaaaacga aacaatagaa aatctcagca aggaaacaag atacaaggaa 68280 aaaaaagcaa atggaaatta tagacctaaa aaatacaata ggagaaaaat aatcattaga 68340 tgggctcaac agtagagtga agatgacaaa ggagagaaat ctgaacaaaa gagagaaaat 68400 agactgaaaa atgaaccatg cctcaggtcc atgtggaaca gtaacaaatg actcaacatt 68460 tgtatcatta gaggcctaga atggagaaaa gagtgacgct gaaagaacac ctgaagaaat 68520 aatggttgaa aattttccat gtttggcaaa agacacaaac ttacagcttc aagaagctga 68580 gcgaacccca aatagcacaa ataaaactat tctttgggaa taaagggaaa ataaagtcat 68640 cttcagaaag agaaaaacaa aaagaatttc tcactagcag aactgccttt gaagactggc 68700 taatggaagt aataaaagat ggaatcttgg aaaaaataat ggaaatagca gaaacatggg 68760 tacatacaac agagcatcac tcccttgata agttctataa gtcatattgg ataactgata 68820 caaaaactgt aatagcatta atcctcaaaa caatactatt taaaagtggg gaaagagacc 68880 caactgaaat taaggtttcc atatctcatt ccatgtaatg gtattgatgg cagtgaatgg 68940 tggtaagtca cattatctat aatgtgatac ccacaatgac cgtgaaaaca actataaaaa 69000 acacatagaa ggccaggcat ggtggctcat gcctgtaatt ccagcacttt gggaggctga 69060 ggtggacaga tcacaaggtc aagagttcga gaccagcctg gccaatatgg tgaaacctca 69120 tctctaataa aaatacaaaa attagccagg tgtggtggca tgtgcctgta gtcccagcta 69180 cccaggaggc tgaggcggga ggattgcttg aacctgggaa gccgatgttg cagtgagctg 69240 agattgtgcc actgcactcc agcctgggca acagagcgag actgtgtctc gaaacaaaaa 69300 caaacaaaca aacaaaacaa aacccaaaca ctaaataaat caagggtctt aaaaatctta 69360 aaaaatgttc aagtaatcat ggaaggcaat aaataaataa ccataaacag aagacagaaa 69420 cagaaaacaa ataataaaat ggcagacctc tccctaacat atcaataatt accttaaata 69480 taaatggtct aaataaaaaa attaaaaggc agagactaac agtttttatt aaaatgacaa 69540 ctatatgctg tttacaagag attcgtttca aattcagcaa cacaggatga aagtaaaatg 69600 atagtaaaag acagatcatg caaacattaa tttaaaaaaa aacaaatggt tacactcata 69660 tcagattcag agcaaagaaa atcgcaaaac agaaaaaact tatataatga taaaggacca 69720 atcaccaaga catagtaatt ctaaatgggt atgaaccaaa tgatagagcc tcaaaataaa 69780 tgaaacaaaa cctgataaac agataaatct cagaagcaga cctatataaa tattctcaag 69840 tgatttttaa cgtatgtgaa aaaaacaatt caatgaagga agaacatacc tagaaaatac 69900 ataaggaacc cttaaaactc aacagtaaaa aaccaaatgg actcttggtt tttaatccca 69960 gagaaataca aactttttgt ttacaagtaa catcacagtt aatggtaaat attatagtct 70020 ctctcaataa aatgaggaat aaagtaagaa taccttctac caaaggttct agccagtgca 70080 atagaggaac agtaataaat aacataaaca ttggaaagaa agaaacctgt cttgatttgt 70140 agatgacata gctgtttact agaaaaccct atgaaatcta ctaaataact actagaataa 70200 gtcaatttag aaaggttata ggatataaga tcaatatata aaaatcgatt ttatttcaag 70260 atagtaataa acaagtgaaa agcagtattt aaaaaatacc actaatagca ttagaaacat 70320 attttaagtt tattcctaac caaagagtac atgatttcaa cattaaaaac tataaaacag 70380 tgctgagata aactaacaaa catctaaata aatggagaga cgtacggtgt tcaaggattg 70440 gaagaatata ttgttaaaat gtgaattctc tccaaattga cctgccccag tcaaggcaac 70500 ccaaatcaaa atctctgcag gctttgccct tttgtttgta aaaattaact gattctaata 70560 tttatatgca aataaaagtc aaagcaacct aatgaaaaag ttgtgggact cacagcatct 70620 gatttgaagc tgcagtaacc ataacagtgt cattttggca aaaggacaaa acaaattaat 70680 agaacagaat ggagaatcca gaaacacggc tcacacacag attgattttc aacaaaggtg 70740 caaaggcaat tcaatgggga aagaaaagtc tctttaacaa atggtactgg aacaaataaa 70800 taaaactatt tagaaaatga atgacatcca ctgtctaaca gcatcacaaa attttattgg 70860 tggtggatca cagatttaca cataaaagtt aaacctatat tacacaatta gaagaaaaca 70920 taagatattt gtggctttgg gctaggcaaa gatataaaag gacataaaaa accataaaag 70980 aaaaaataaa ttagacctca aaaaatgaat aatttctgct caccagaaga cacttaagaa 71040 aatgaaaact tggagaaaat aatcataaac tacttatcag aaatgggcct tttatataga 71100 atatacagta ttccccactt acccatgggg aatacgttcc aagacctcca gtgatgtctg 71160 aaattgcaaa tagtactgaa ccctgtatat actatgcatg atttattttt ccttcttcac 71220 aatttcatag atacaatact catttttacc atagatttta gcaacctcaa catatgattt 71280 ttaaattctt tccttaaagg aagcactttc cagcttctct ttggcatata tattcgaatt 71340 tccaacatca ctgctcttgt gctttagggc cattattaag taaaataagg gttacttgaa 71400 cacaagcatg tgatactgca acagtcgatc tgataaccag tagactaaaa gtggtgggta 71460 gtctagacaa caacgatata ctggaaaaag ggataattca tgccctgggt ggaaaggtgg 71520 gagatttcac catgttactc agaatagcat gtaatttaaa acttaagagt tgttggctgg 71580 gtgcagtggc tcacgcctgt aatcccagca ctttggaagg ctgaagtgga agaattgcta 71640 gagtccaggg gtttgaaacc agcctgggca acatagtgag accctgtttc tacaaaaaaa 71700 taaccaacta aaaattagct gcacacctgt agtaccagct actcagaggg ctgacgtaag 71760 aagattgcat gagcccagat actcagagga ctgaggtaag aagattgcat gagcccagga 71820 gtttcagttt ataacaatct gtagtcatgc tactgcactc cagcctggat gacagagact 71880 ttgtctcttt aaaaaaaaaa aaaccaacga accaaccaac caactctccc tgccctgcac 71940 ccgccaacac acacatacat caaaaaccct gaattattca tggaattttc tacttaataa 72000 atatttttgg accactgctg accaaagata actgaaacca aaaaaaagca aaactaagga 72060 taagacatac tgctatattt taagaaaata tctatagtca atagaaatac aaaaatccaa 72120 tattaaaaat gaggaaaaga cacttttagt taaatatgca cctgctatat gctttggaaa 72180 ctccactcct acatgtttgc ccaggagaaa taaaacattt ccacaataag actacacagc 72240 tttattcaca atagtcccaa actggaaaca atccaactgt ccaccaacag gtaaaaaaaa 72300 aacactttgc gtattcatat aatgcaacac tactctataa ttttttaaaa ggcactataa 72360 atcaatgcaa taacatggat gaatctaaag agtcttcatg cagtacaagt acataagatt 72420 ccattcataa gaaattctag agcagacaaa agtaagctac agtgacagta attaggacag 72480 ttattgtctg ttctaatggg ggatggagat tcactggaag ggaaaacatg ggaactctgt 72540 gctgatggac atagtctaca ccttgactga aatatggtta cataaatgta atttttaaaa 72600 actaacccaa ttaagccctg ggtatttcac tgtattcaaa ttttacccca cacaacatcg 72660 acaccaccat tattaccacc acattgataa cattcagaga gcagttaggg aatcacatta 72720 ttttgaaaat tagtaagtaa tgggaaagaa ttaagcatta tcgtatatga tatgtacata 72780 tttatataca tgtatacaga tcctatatgt ggatctgtaa tttagggtag tcatagagtt 72840 gatgagaaag agtttttctt aagaagtatt acaggtaata aaggaaggag gaataaagaa 72900 ttcgagtatc acaattttgt aaccctcaat gaattagcag atctaggcaa tcagaatcca 72960 cgataaaaat tactagaaaa gacagaaagc gagtgagact tttaagttat tcctacaaac 73020 caacatctat gaagtatttg ggaaggaaat aaactctgaa tctgtttttc gtttttttga 73080 gatggaatct cactctgttg cccaggctgg agtgcagtgg cacgatctag gctcactgca 73140 acctccgcct cccaggttca agcgattctc ctgcctcagc ctcccgagga gctgggatta 73200 cagctgcctg ccaccaaacc cagctaattt ttgtattttt agtagagacg gggtttcccc 73260 catgtttgcc aggctggtct caaactcctg gcttccggtg atctgcccgc ctcgggcgtt 73320 tttgcatgta ttttttcagg tgctgaaaaa gctctccctg atttcatttc ttgttgactg 73380 cttagagaca tctttccaaa tgtccttcct tgtcactttt tcaaagttag gagcagggat 73440 tgcacgtttt tttgattggt aatttttgtt tcaaaggttt gattcagatt cagagttgat 73500 tttgctaggt atggtggctc acgcctgtaa tcccagcact ttgggaggcc gaggcgggcg 73560 gatcaccaga ggtcaggagt ttgagaccag cctggccaac atggcaaaac ccttatctct 73620 actaaaaata caaacattag ccaggtgtag tggtgtgcac ctgtaacccc agctactcag 73680 gaggctgagg caggagaatc acttgaaccc aggaagcgga ggttgcagtg aactgagact 73740 gcgccactgc actccagcct cagtgacaga gcaagactgt ttaaacaaac aaacaaaaaa 73800 ttaacaaaat cttatttcta gtggtttaca tattaatgat gctggcaact tttagttgaa 73860 atgtattaaa cagcctcgca gtttttattt ttatgaattc tgcatacaat aaataaatac 73920 caaccaaaat atctatacag gcatacccca gagatactgc cggttcagtt tcagaccatg 73980 gcaaataaag tgattatggc agtaaagtga gtcacacaaa tttttttgtt tcccagtgct 74040 tataaaagtt acgtttacat tatactgtag tcaagtgtgt aacagcattg tctaaaaata 74100 agtacattat cttaatttaa aatcattgct aaaaatgcta atgaagtgag cacattttgt 74160 tggaaaaatg gtgctggtag acctgcttga tgcagggttg ccaccaaaaa aactcagtat 74220 ctgcaaagtg caataaagtg agatacgcct gtaatgtctt ttttctcttc tgttattaca 74280 agcactactt taagtcttca actaccgaat acttgtagac tatttaatga attaatattt 74340 tcatcatatt tatattgaga aaattaagaa gctgaattta gttagaaaag gtttagaata 74400 tcatcaactc ttgaggatga gttggaagct actttatctg tcatttttca cataacacta 74460 gtttgccctt caaatcatac atttaaaaat gatcttaaga tacataccaa gtagggatta 74520 tgttgttata aaaagctaga agtaaaatta agactttaat ttcaaagata atttctctat 74580 aaagaatagc acaagatatg ttcaactatt ctcagagatg catcaagata tgactttttt 74640 tcctactaga aattatatct atgatcaatc atattacaga gatattgctg ttatactcct 74700 tgtgactgat gaggggggtt tttcctatca ccatgttatc ccaacccttt aatgaatcac 74760 ctttgaaact cagaacaggt agcagcacag aggttgctaa gagtaaatac attcaccact 74820 gctgccagaa atgaccaacg gtgcaccaga aagaagaaat actggtgaat tcccacatac 74880 cacgacgaac aaccttataa aataacagaa caaatgaata taaagtaaca tacagccatc 74940 ccttggtata tgtgacaggg attggttcca ggaccacgtg tgtataccaa aatccatgca 75000 cgctcaagtt ctgcagttgg ccctgtgaaa ctggcatgta tgaaagtcag ccctctgtat 75060 atgcaggttc tgagtcccac caatactgaa tctgctctta gttgagaaaa aaaatctgca 75120 tgtcagaggg cccatgaagt tcacagctgt gttgttcaag ggtcaactgt aatataaaaa 75180 taacatttat tgctagatag agttgatatt cattctagtg tttatatact tgagtcttag 75240 agcaatagcc tttggagaca acttccagga aggtacgtgt ttgcatgcct tctcactgca 75300 atccatcagt agctgccact tgaaccagtc ttagcagggg atggggaagc ctatgtcttt 75360 cagaattgga tgatgtagta cacagaagta gacagtagag tagtaagggc atttgcttaa 75420 aagcagatag aactgggaac ctctacatct ttctgtgaga attcagggct tagtttttta 75480 gggtgtaaaa tggaaatact agtatgtatc tggacatatt atcttaagaa ttaaataaaa 75540 gactaccatt tcactcaaaa agtgcttgat cctgggaagc catgtaacag ttcacaaatg 75600 cagagttcaa aagaaaggaa aaattgcaga catggtagcc ttattttaat tatcttctaa 75660 ccagcagtaa gcatactcta accagtgagg aatactagat aatccatacg ccaaatgcag 75720 gagattacat gagacttata tataacaaca cttcattcat gaaataaatc acaagattag 75780 ctctgaaaaa tggtgattat attacaaata caaatctaag tatatagatg acaatttgtg 75840 agtttgctta tttgggaatt agtacctaga gataaaggtc tgaagcaaaa tcacacaccc 75900 ctttggtgaa tcaaatcttc ctctgaagaa ctaagtacct cacctaatca gaacagagtc 75960 cctggtatag ccaccgtcat attctgtagt ttcttctagt gcttggaaat ctagattctg 76020 caaattcaag aaaatatgtc ttagttatct gctatactac tgtatcatta caaacaataa 76080 atcgatacat gactttttgc agacacctgc tttcttaccc ggcttccaca tataagcaat 76140 tcaatttctt ctggtctgaa taagtacttt aagggagatt cattggtcac catatgaaaa 76200 cctctccgaa aagccttgaa ctgtttttct actgatttat tgagaatgta gtcagaataa 76260 agattgacaa attcctgtag aaaacattaa tcacaagaac ttcttataat atgctatgca 76320 aacaaaacac aagttattgg gctgcatagc tttttaattt ttccaagaaa aaaacattca 76380 agaatattct taaaaattca attttacacc tacttcttaa caatttcaca attctctgtt 76440 atagccaata ttaagctatg aaaaggccat atacataaaa ctgtcaagaa tattcttaaa 76500 aattcaattt tacacctaca aagaaaacta cttcttacaa tttcacaatt ctctgttaca 76560 gccaatatta agctatgaaa aggccatata cacaaaactg tcatacttat aaatgtcaat 76620 ttcgataatg tattaaacag aactgaatat aaatgctgga gacgcagaaa attctttagg 76680 ttctctcaac taggtatgta aacagacaca tttaaaccat gtatccatct atttataaat 76740 gccaaccgtt ttaagagagt acaatatatt tgatttaagc aaaccaggaa gtcccaagtt 76800 ttctaccata gaatatttgg taagctgcct actgtatcca gttcagcaaa aatgtggaag 76860 tactgactga cacataaact actgtatcaa atcataaaag gaaaatgtgc tttgtaccct 76920 tagtgtgtat aatatttaat caaaaaatta tatcaatata aacatgtttc ttaaaggtat 76980 actatatatt tgtcataatt ttttgcttgt tatgttctgg gttattccca ttcccgatga 77040 acacatttta gtcaatagaa acccaaatct gacgtaaagt atacttttca gaaatgtatt 77100 tttatcacaa acaggatata catgtgtaaa ttaaatgtaa tttttatttg ttctgtgata 77160 aagaccttaa tcatgaggtt cctgcttaca gcttaataca agaaacaccc tgcttcttgc 77220 tttatactac aaccacactt agctattaac tatctcctgc ttcatgtcct ctttctctaa 77280 aaggggcttt agtgcccaac tgtgtgcttt cataccaact tatatccaag atttagaaaa 77340 gtggactcta gcatttacat aaacttagtt acttgttttt tttttgtaca gactatatta 77400 gatacttctt taaaaattat aagcatacat gctttgaaag tgttaatgaa gagacaaaat 77460 gtgacataaa aacatttatt accttcctgt tttcatttgt aattggaatt ttatcaccat 77520 tttcctttag atcatacatc attgggttac caaaaagatc tgtctgtgat atctggaaag 77580 tgatcatcat gtcatcttcc acattccctt catactccaa taaatctttt aaactctgat 77640 atagaaccta gcaaccagaa atggtaaatt gaggccacca tagaactaca aaatacaaca 77700 aataatttat atcactcttc ttagaagaca acaaaaatct tatcaataaa aattgtaaaa 77760 agtgtagaca gtatccctcc agtcccccaa atagtttcca acctataaaa gaaagattgt 77820 cagtcactgt gatgtcccat tctctgctga gaaaccccat accaccaatt tagcaataga 77880 attcacactg tgctctatga gaaattctgt ggtgtctcaa ggtgggggtg ggggtggtag 77940 gagcaggcac actcgttgta actaccaaga cccttagcca gggctactct gatttttacc 78000 tatctcttaa gatttcacta aaacacaaac aaaatgttta gaaacacttc tctatgaaat 78060 caatcttaca aaagcttcgt gctgacagca atatataaaa atgtccccct ttgagttttt 78120 aagtgtttct ggtacttcgg tcagattaaa acatttttat cttattgata agagtatcaa 78180 caaagattct aaacaaaaac tttaaaattt tgacataaat taaatttttg catttaaata 78240 aaatctaaga gactgaatta aaaaaatgac aaagaactta ctgggtgaga gtctcccaag 78300 tcacgaaaag ttcctttttt ccccattagc ttcctgtaga caaccatggg aaaatgtaca 78360 tccagtatac agttattgta aatagccaga cccagtacta tgccaatcag agtaaactga 78420 ccctcagttt caaaagaaga tggattaaac caaaacaatt ttgtagattc atcgtatgtg 78480 aacataccta taagaaatga tttttaaaaa tacattactt ttgtatttta ttaaggactg 78540 atgaataata caaatataaa cttaaaataa ttatgcatat aaaacattta aaatatatgt 78600 aattaggcat gcaacattga tttctattat attagcactt gagaaaacaa tgtccacata 78660 tatctgctat aaattggggt gaatggtgat atgtaatttt atgaagccaa aggaataaag 78720 tagtaagtaa tttggtggca tcgggtagaa aaatacgtta attaaattca agctttctaa 78780 ttttctacta acacataaga aaagttatat tcatgcttta tccacccata gctgaaaaat 78840 aaacataaaa aaacaaaaaa tggctacatt tccaaagtgt ttcatttata aaaatataat 78900 tacttatatc tgtaccacac gtactatttt tgaaaacaat ttttcatttt tttccttgag 78960 atggagtctc gctctgttac ccagggtggg ctggagtggc acgatctcag ctcactgcaa 79020 cctctgcctc ctaggttcaa acaattctcc tgcctcagcc tcctgagtag ctaggactac 79080 aggtgtgcac caccacgcca gctaattttt gtatttttag tagagaaggg gtttcaccat 79140 gtttgccagg atggtctcaa cctcttgacc tcgtgatctg ccagcctcag cctcccaaag 79200 tgctgggatt acaggcgtga gccaccacac ctggcctaaa aaacaatttt taatcacagt 79260 aaagaaaggt tcgttttttc aaaattagac aatggtgcca tgaaattttt ctagcatttt 79320 cctaataaaa tcagatgatc tgaaatacat aaacctggat aaatctgatg aacttagata 79380 aacaaagcta ttcaatacac atgttaatta tgggccaata cgtaaaagaa aagtagtttc 79440 gtagtctttc aatttcacat ggtcttcact atgcaagccc caatcatgga ggcttttttt 79500 tttttttttt tttttgagac ggtctcgctc tgtcgcccaa gctggagtgc agcagcactc 79560 agcttagtgc aagctccgcc tcccgggttc atgccattct ctggcctcag cctccggagt 79620 agttgggact acaggcgcct gcgtggaggc cttttttata tcactcattg gaaaattggg 79680 gcccggtgtg gtagttcaca cctgtaatcc cagcactttg gggaggctga ggcaggcaga 79740 tcacttgagc tcaggagttc aagaccagcc tgggcaagat ggagaaaccc catctctaca 79800 aaaacacaaa aaataagctg ggtgtggtag catgtgccta tagtctcagc tacttgagag 79860 ggtgatgcat ggggatggtt tgagtcttca gcctgggagg tggaggttgc agtgagccga 79920 gacagaacca ctacactcca gcctgggcct cagagccaga tcctgcctcc ctccaccaaa 79980 aaataaaaga ttaaaaaaaa ggaaaattgg aatctttgga atgagtacta ctaaaaattg 80040 atttcttccc ttttaaatga ctaaggaaaa aaattttaat tgaatttaaa tcattttact 80100 acatgtttag ttgctactgt gaaacaatga aaacatctta agaattaagt ctgaaaaaaa 80160 tctgtaattt ccaatagaaa agtagagctt agaaatcaga aatcaaatta tacagtatat 80220 aagtatttta acctgtttat aagaatttta aaatctttga aaatgtcatt gtcactttaa 80280 gtttaaaaat aaggagcttt aacatgtttc cttgatcact aggagtatga attaagctta 80340 ggacattttc tgaatgcaaa atggtttgaa aattaaacaa ttcatatttg agtttcatgg 80400 tttctatcta aacatttttt ttacaggcca agttacaaca tccatggaaa tgcttttagt 80460 tataagtatg gtattaacag gatcaagaac agctgacaaa taattacaat taataaattt 80520 gttcaagctg acaatggtgt gtctaaaaaa ttaatgaatt taataaaatg tcacaaatgc 80580 ccttccttgg aaccaagagc aacaagctat aagttaatca gaatataact ctgaagttcc 80640 attttaggca cattttctca tgttccaggg agaaaagcac cataacctcc tggtaaaata 80700 ctcctttttg atacttctac tgccatcact tcagttatct tactggaact gcttaatcta 80760 tgttttttct tacaagtatt tctgcatata atgcaagtat gctttatagc taaggtttaa 80820 catttctaga tacatcaaaa gctagagcta aggtttacca aatttaagaa ctttatgaag 80880 tttataattt tctatctcaa aaagggcgtc gtcttatgta tctctgattt acttagaaca 80940 aactacatac aaatggcata gctttttagt tattaataaa acactagcta gattatagat 81000 aagggatgcg tgtgtgtgtg tgtgtgtgtg tgtgtgtgtg tgtgtgtgtg tgtgactaag 81060 aacagtaaca gaaaggtcaa ctcaattaga atcaacaggc tataacagct caaatctcaa 81120 agctgaaggg aaatgacata cattattcta tgcacactcc tcacaattct gatggtacct 81180 tcagtggaaa ccttttcctg taattgtcat gtactcaatt ttaaacgtaa gcaagctcag 81240 ttactaagtg gttatattta cagtagaaac tgaaccagtt cagaattatg aagttaagta 81300 gactacccaa aagactgcat cttttccctg ttctacttta tcacaaaagg gaaaaaacta 81360 aaattctgat ccttcacttt caaatttcca aatcccatca gcctttccca aactgtgttc 81420 aataacaact cttctgttag ggcagaaaaa gagttctgga gttcaaaaag tttgggggaa 81480 acactaccta tattaagccc caagaaatct tatagcaaat aaacctaatt aatgtgatat 81540 cagctagtgt ttctgaactt tgagcatgac atacttgtga gacagtctct caatactctt 81600 caaaccattg ttctttgaag ttcacaggtc aggaaaaccg tgagtttgat gatggtttta 81660 gacaacaaaa agcaaagaaa tccctccaac tgttccaata taccattcta aagtgctttc 81720 aattcagttt accaaagaga taatttcctt cattagaata ttccttctaa gaaataaaag 81780 aatttgaata aattagtgat acaaatcagt tcctaaaacc tacaaattca gtcatgatgt 81840 gtgattctgg gtaatccata ccaaatcctt cttttgctgc tcttcatagc tgaaaatatt 81900 tacaaagtaa gataaacaaa taactaactc aaaagatgat acgacaccat aatcacatta 81960 ctaatgtatt taccaatatc tggattgaag atttcctcca caaccagctg aaaaaattct 82020 ttggaaacac ctccctcatc aactccttgt tctccttcaa attccacata caactgcttc 82080 ttcaagtctg caggattttc catagcgatc atctctagct agtgattgaa aagataaaca 82140 tgaaaagaag atgattgcta gtatcaggaa aaaaacaaaa taaaaacaag gagtaggatt 82200 aggaaacaaa tacaaatttt tgactttttg tatgtaaatg gaaacagaaa gcaaactgat 82260 aaaaagccag tgaagacaaa gattcagtct taaagataat caaaaagaca gacacaaaac 82320 agacactagc atagtaaaaa gctaacttta ctgatttgtt atgaaattaa catacaatta 82380 attaagattt tattacttgt gtgttaagtc tggactacac aggacatgga aaagcagcta 82440 aatcatttca gcaaaaacaa tggagtagag gtctaacctc aaaattgttc attagtagtc 82500 ctttattaga atagaaactc aagggttaag tcttagtatc tactaagtca taagtaaaat 82560 atttcaatta agaaaaatac actgaatact aaagcagttt atggtctctc acagtaagac 82620 ttagtataaa ttaccacctt ttaatggact agaacccatc ttatatccac atttccttaa 82680 aaacaggtga gacataacct tactcatgtc cttactcttt tttttttttt ttttgacatg 82740 aaatctcact ctgtcgccta ggctggagtg cagtggcgcg atctcagctc actgcaacct 82800 ccgcctcctg ggttcaagca attctcctgc ctcagcctcc tgagtagctg ggattacagg 82860 caggcgccac tacgcctggc taaatttttt atttttagta gagatggggt ttcactacgt 82920 ttgccaggat ggtcttgaac tcctgacctc atgatccgcc cacctcagcc tctcaaagtg 82980 ctgggattac aggcgtgagc aactgcaccc agcccttatt cttaaattgt aagttaacaa 83040 actttagtgt ctagcatttt ctcaactata aatcttttac caaatatttt tgtgtaccta 83100 tagaattatg aatatacagt aacctcattg agattaatca taaaatcaac actagattcc 83160 aatattaact gtttatactg cattttgttt gttttacttt atgtatctaa aatttgctaa 83220 cagtatgact gtatccagta catggatgga tactgtatct agtacatgga tggatactgt 83280 atccagtatc catcatatct cctaacttgc cttcaaacat ctgttggctg gttaaaaaaa 83340 tttaatcttg gagatgaaaa tttaccaaaa caggatatta aatgttttca ggttattcca 83400 actatttcaa acagaatttt aaaaatggtt ttgaaaaatg caataatcac tgaaacaact 83460 gtaacacagc actatagtag ttaaagtaat aatactcatt tggacaatct agtctgtcta 83520 caaaaaataa aatctcataa attaacgcat caggtcaggt tgcccgagag cattgttttt 83580 tcaaacttgt cacctgcaac tcattagtgg gtagtctaat ccatttagtg gtttgcaatc 83640 agcaatggga aaatcagaat gcattccaca tagtaatgga acctactgtt ttgtgaaact 83700 tttgtttcaa ttagatgtac agatggataa gcatgtactg ggatgctatg taaaatacta 83760 gggattgcag tcaaagagtt tgacaaaact agctgaaatt atcttctggg tatcttcaac 83820 tttagggtcc tattctgtga atttagtctt tagctttaaa taatgtctgt tgttgttcaa 83880 caccgatctc taatatttac aaaatcattt ttaggccaca cagtttactt ttagacaatg 83940 ttttgttatg gaaagaccaa gagtcagtca gaattcacct tactagtccc aactctcact 84000 taccataact tttaaccttt aaactttagc acgcgattca attaagcctc agtttcctca 84060 acatactgta agttgtgaag gcttattaag aatatatgag aacgagtgtt accttttaaa 84120 atagttttgc tctctgaaca acagatttgc aattttgtgt ccccaaagga acttgatata 84180 gactagttcc aagatctaga gtcaaacaaa tgtagatgtg aaaataacct tggggaaaaa 84240 aatagtttca gttggaaacc tgtttcaagc tacggagtat acagaattct gaggagacta 84300 aaattagaat taacatctta gctcaaatgt gggaccaggc caacattcca tattgccatg 84360 taatccattc tgagtttcct tatgccagtt cccaactggc taggtgttaa agatgtaagt 84420 cagtgtttat atttaccttt acatccaaag gtatacttgc ttttatcaaa tataatgtat 84480 tccaaagtgg ggaaaaaaaa ggttatctgg tatttagact gtgcattcta cagcttttcc 84540 ccactaacat tcatagatga gagctgactc cttatcaatg taaaaccttt taaaggatgt 84600 ggtggtgaat ttctacagga ttgagaggcc ctgtgttcta tctagtctta gctctaccta 84660 agacatgtca aatgataact gaagcaaatt tatctttatt ctccataaaa tattacatgt 84720 ctgtccactt ccactgatct ctattctatg ctccccacct tggtgccaaa agaatgtaat 84780 gcaatgcaat atgttctatt gtaaatgcaa acatacaact ttacctctct tatttcatct 84840 gtaaaataac cataataata tagtaataaa ttaatgtatg aactgcttag attaattccc 84900 tgcataaagt tagtgcttaa aagtactagc tgttgttgct gttattttat tggttctaaa 84960 atattttctg aaaacctacc atagcattat agaacaaaaa tattccatga atacagcaac 85020 aataatatat agcacttttg tagcatttca cacatagcaa ctaatttaat cttcacaaca 85080 cccttatgag gaaggaaaca ttaactccac tttacagata aggaccccaa gatactgaaa 85140 ggtgaaataa cttcaagtca cagtaagtca cagtaagttg tggaacagag atactaatcc 85200 aggaaacaag ctcttaacta ctatgcttta ctcactctct tcaatgacga ccaaaaattt 85260 tttttttagg attatgagtg atttttattt tccttattct tttccatatt tttccatttt 85320 ttacaacaaa tacatttttc agagtcagaa tgtgttcaaa tataaatatg taaaaagaat 85380 aatttgaaaa gtagttggta actgaattct gtaggcaaaa attttgttat tacctatttt 85440 agattaccat tctggtacac ataagtgatt tcataaaata ctgtaccact taagaataaa 85500 ggctgggcgc cgtggctcac acctgtaatc ccaccacttt gggaggccaa tgcaggcaga 85560 ttgcctgagc ccagcagttt gagatcagcc tgggcaacat gatgaaacct tgtttctaca 85620 aaaaactaat aaataaataa ataaataaat aaataaataa ataaaaaata gtggggggtg 85680 gtggcatgcg cctgtcatcc cagctacttg ggaggctgag gtgggaggtc aaggctgcag 85740 tcagtagaga tcgtgccact gtactccagg cctgggtgac agagttaaga ccctgtctca 85800 aaaattaaaa taaataaaat agtaaaaaca gaatacataa atagccttta aaactatttt 85860 attttaaatt attaacacat aaaatttagc aataaccatt ttgataaagg ccattattgc 85920 ataaacagct gtactgataa ttctttttct taaaaataac ctccatcaat tgttcggtca 85980 atttaaaaaa gatttaacaa ataaactgta aaggtgtatt ctttacataa tagctatatt 86040 atttaaaatt gtatgttgtt gtttaaaccc aaacctcacc ataaaactgt attttttaag 86100 tcagaagttg ttttaaatgc attaggatat ttgaaatttg gaggactatg tctaaacatt 86160 ctgaaaagga gaacgtgcat gcatgcctga atttatttac aatacacacg tggattttta 86220 gggttttttt tgtttgtttt tttttttttt ttgagacgga gtctcgctct gtcgcccagg 86280 ctggagtgca gtggcgcaat cttggcgcac tgcaagcccc gcctcccagg ttcatgccat 86340 tctcctgcct cagcctcccg agtagctggg actacaggcg cctgccaccg cgcctggcta 86400 tttttttttg tattttttag tagagatggg gtttcactgt gttagccagg atggtttcgg 86460 tctcctgacc ttgtgatctg cccgccttgg cctcccaaag tgctgggatt acaggtgtga 86520 gccaccgcgc caggccaatt tttaggtata tttaaaagta cagtgtatgt tgtatttatt 86580 taacatggag actagcaaca gacagagatt actggggaaa aataaacaaa aatatcctgg 86640 atataatcat atctacctct tcactgcgta acttcctctt ctttaagact cttgatttca 86700 tcaattgctg gataaaatga tttttaattt ctgaactttt taattggcca tgatgatgaa 86760 atcctaggga gttcattttt taaaaaaaaa atctgacctg atatcaaagc atttgcagaa 86820 tacctagcag gatgacatct taatatcaaa atatgatatt actagactta caggaatcaa 86880 aaggaaaacc ttatcactta aaatcttata gttttctgag ctattacatc aaatcaattc 86940 ataatttttt aaaaaaattc cttaatacca tgaatattta agtagaagca ataatcagat 87000 aaaagagacc tctaatactt aagaatgcct gggatttcta agaaaggcta gcttcaaggc 87060 cgggcgtggt ggctcatgcc tgtaatcccg gcactctggg aggccgaggc gggcggatca 87120 cgaggtcagg agattgagac catcctggct aacacggtga accccatctc tactaaaaat 87180 acaaaaaaat tagctgggca tggtggcagg cgcctgtagt cccagctact cgggaggctg 87240 aggcaggaga atggcatgaa cctgggaggc ggggcttgca gtgagccaag attgcgccac 87300 tgcactccag cctgggtgac agagcaagac tccgtctaaa aaaaaaaaaa aaaaaagagg 87360 aaaaagaaag aaaggctagc ttcaactact tcagtcaact tgaggcttaa actattgctt 87420 gagatttcca gattatccaa attaattttt tcatgttcac gataaacaca tgaagaaaag 87480 tctgttatat ctcaaatgta gtttaaatgt ttgggtaaca ccaaatcaca taatcacgtt 87540 cgtccatgag acctggaatc ctgacttcta tttccaattc tgccattaat ttatgtaggc 87600 tggaatctct tttagatttc attttcctca catgtaatac taagtttgat gtttcattgt 87660 cttaaattat tatataatgc tgaggatcta tgtatatata ggcttcattc tctcattcag 87720 tttctgagaa attactttga gggcataaac caagcatatt tcttggtttc atttttgatt 87780 tcaattagaa taaatcacaa gaaagaacaa tggaaattac atgttaacca caatatagtg 87840 tatgtgtaag acaaaattaa acatacctag tgcagcacag aataatctca tttttaaagc 87900 tctgtgagtc aatgaataaa taaaagaatt acgttcatgt ttcactagta agagtgttca 87960 ccaatgctgg aagctgggag ctgaaaatgc tggaagctgg gttagactag gctattagaa 88020 accagataaa aagggccagt gacttttaga ggggattttg cagaacctcc tggtagtggg 88080 gctttttatc tgtgccaatc acctttatct gtgctaattc ctatttttga acttccctat 88140 tcaattccac atctcagcca ttccttttgg tttttagata tttatgtgaa atgctagaac 88200 tccctgacta attggaacca agtttcacat catcatcatc ctctattcca agcttgctgt 88260 ccccatgatc ctcttaaaaa tctgagtttc caaaacacat aaacatactt gtatatcaaa 88320 atggcctttc tctttctctc tatatatgca cacatacaca cataaacaca catgcacaca 88380 cacccccacc tgagctgaac caaaggccat cttcccaaat attggagtct ggctttatca 88440 aaatatttgt ggagtattac cagaagttca gattcatagg ctctacaata cagcttctaa 88500 tctaaacctc tagaggttag ggccctggat tttatttatt tatttattta ttttttttaa 88560 acaattttcc cattcagatg tgaaggcagt ttgagggacc tcatgatggc aatactatat 88620 tcttccataa acttataacc tctatcttct cctttaagaa gtaatttaaa aaatcttaat 88680 acatactatc attggaagtg cttcatctaa gaaaaatgag aaattatcta cttgtaaaag 88740 aacacacaaa tgggtatatt tacatatttg taaatatgta aatatttaca tatttgtaaa 88800 tatgtaaata tttacatatt tgtaaatatg taaatatttg catatttgta aatatgtaaa 88860 tatttacata tttaaattaa attaatttac atattaaatt aaattacata tttatattaa 88920 aaatgtaaat ttgtaaatat ggttttacat atttgtaaaa acctcatcac attaggaatg 88980 tcattcaaat gaaaggtgaa gtctaagctc atgtttatca ctgtactgtt ttctaaggaa 89040 caataacgaa aaaatactga aaataagtcc taggggaact atggcagtaa gttaaacggg 89100 tagggtgggg gtgttcttaa gcagttctaa ggtatttgtg aagagacaac ttatattcta 89160 ttgattctaa aattcacttt tttcacatta tctctgaaat cagattacac catacaaatg 89220 atagcatctt acaatgaatt gctggtattt ttctgtctta gcagtaataa aatgatagtg 89280 tttcctacaa tcagagatta gtgaaaatac tatcaacatg aattcttctc ttgtcatcaa 89340 agacaatttc tctaaaaacc tcaggaaaaa agctgctagt ctggtttgaa tttcacaata 89400 tataaaagca atgaatatat ttttcttttt taaaaaaatc cacaattatt aattcaagtt 89460 accactcctc aacagaaaac atacaagagt ctcatatatg aagtcactat tttctgggct 89520 tgatttctaa actaaggagt ggataactct aaggtttctt ttagctctta aagcctagga 89580 tcccataatt ttatttatca atattaagct taccacaaag tttctcattt cttcttttcc 89640 acccaaccct gctatacaat tccaaaatta gcaagtcata aaaaagtggc cactagtttg 89700 ttcactgtga tatataagaa tgaggcttaa aaagcagaga tccttgggaa ataagatctt 89760 gaaaaattca tcacttttga gctttcatat gagagaataa tcttaaacca ctttctatta 89820 tagaacttct actatgtgtt actaaaatat gtggctttat cataatcatc acctgctgtg 89880 aatacttact tcaaaaaatt acacaggtta tcaattttac ttataagacc tatttcgatg 89940 ctggtttttc tagtcttttc acattctgtt atttttttaa aaaaaagaaa aggaagaaaa 90000 agcaagggag aaagaaagtt aagagtaaaa tctgcttagt gtgagcattc agagccccta 90060 aggaagcttc tctgtaagca tcatctcttt ctattttcac agtttattaa actgcctaac 90120 acacatgatt tctgaagtga actgcttttg tgggctggca atattcaagt acatatacta 90180 tctagtgaat cctgatttat gataggccac actatattat ctaattttga tataattaag 90240 cagaacttgc taaaaacaag ttaccataat taaagagctc acagttaatt ttacactaac 90300 acctaaggct ttaaaagcag ttgtttcctt aaaattctag aatagaattt aaaatataga 90360 ataaagtata taccaagtac ttaaactttt gtttttagtc ttgctttact agagaaaaaa 90420 atgggggact gaggaaaata agactgagta gacttctgag cgaaagacag ataaggaagg 90480 tagacaattt tttgaaccct ggaatgattc ttacagtgta atttcattgc cttttaaagg 90540 ctagacatag cttttgatga agacagctga agggatctca cctcaagaag ccaaacataa 90600 agtatgtagc tttggcattt gcagttctgc tccaacaatg gatagtcata gacagacctc 90660 aacatacctt tcataaaaca tcactcacat tcttataaaa taccctatca ttctgctaaa 90720 ctatgtaaag taaggtgctg gctgccttat gatcagtcat taagtgtatt aattattcat 90780 gtgtctcaaa actatgtaag tgaaataaaa agggtaccag aaagcaagca ataataatga 90840 cttcaggcag ttaaagcccc cttttgtctc tgctagaaaa ccacctgagt tgcttaaata 90900 atgcagaatc tttctccaac actataaaca tatctgacat taaaaaaaaa aaacaaacca 90960 gtaacaaaaa aaaaaaaaac acacaaaatc tctgcaattt ttaatttctg agatgtcaaa 91020 taactttttc caccgggcta cagctttatg aattctcgaa tttagacaat tctaaaacta 91080 aaatttagac attctaaaac taaaatacat tttaaagtaa aaatcacatt tcctagttgt 91140 ctgtgtcaga caactttact agtatactat agtattatta actaccttaa tttttgttga 91200 cattaaattt tacttgaaga tgataaaaaa gtagcagcaa tgacagggat agctaatact 91260 agaaatacaa taaagctctg cgataatgca cctgagacaa atgtaaattt tggtgaaatg 91320 tgactgacga ctgctttctg tcttctggcc actcttatat tcttaaacag atacactaaa 91380 attatcttgt ggaggaaaga aaaggaacaa atggcaaccc catctggaaa accaggaagt 91440 taggatgagt acctgagttt ccagtatttc cctgctcaat ctccctggac ttgatgttac 91500 aggcaccact aatccccaga tttttggaat agctgctgtt ttccagaagt tccaagaccc 91560 agagttgtct ctatgaattt ttaagtggga agaaactacc acagccaggc agtgccgtcc 91620 acacagggat attctaagtg gcccagcagg actcaactct tactggcaac aggcactgat 91680 ctgccatggt cacttcatca agtccacaat aatgcaactc tgaattttac acgatggaat 91740 tttttggaca ctacctataa ttttatggta tggttttact gtaccattac tcccagttca 91800 agactgcaca tccacactta ttattgggta tctccacatt tctcttgttc tggtctttgt 91860 ccaacactct attctcttct gaatgaaaga aactttggat ttagttttca agatttagaa 91920 aacccattct ttttcaaaga tagcatgacc attatataat acaaccgata ctttgtagaa 91980 cacatctata aacttgcaca ggaacaacaa aagtataata cttatataag atcagaaatg 92040 tccatgtgtt cctatgctat atggtatcat ttttttcagt cacttttaaa atgaattcac 92100 tgaactgtat catgatatcc ccattattag gtttttaatc tagcagccca acttacccgg 92160 acaagtgcat catctatgat atggtcacgt ctaactttga gtctcaaata tggattcaac 92220 tgctgtcctt gaactaagct gtagagaaca gtgattcttc gttcactgta catgcgaatt 92280 ctattgtcat aatataatcc caaattcttt gtgacagcat tcaatataaa gggacatgtc 92340 ataaaagaga atttgttctc tgtttctact ttgaaaaaag tataatcttt atccatttct 92400 agaacctcat tcagtggttc attaataaac tcttcaaaag ggataagtgg ttttcgacaa 92460 tccagggttt taacaccaag ttcagtttcc agggggtcca ctcgaggacc tttcttgttt 92520 cttctttctt ctcccaaaag ttcctgaagt gtcagctcgc tggactcagg gatgggctct 92580 tcatcatctt cttcattgtg atttgtgtcc acttcccctc ccactacatt tgcatagtaa 92640 accattttca agcacttcga agcagcaaca atggcatcat catcattcac tagatttcga 92700 ctgttaaatt cattgcttat gactttataa gtaataagtt gctgaaatgt ctccatcatt 92760 ctccgaatct ggtctgcatt gtatttagac cacagtctga tcagttttcc ttgggctgca 92820 aggggtagct tgctcatcgc tttgcaaaat aatggcaaag ccatttccag atattcagga 92880 ctgtggagat ttctattctc cattacgata atgaacaaat tcagataatt aggatctcga 92940 gagtatacat tgtgatacgt caagtcacat tccacgttag gtgacaaata tacaagtgca 93000 ttgagaaagg cagtttcaat tttttcatta gagagcaatc tggtgtagac ccttctaatg 93060 gcatcaatat ccacagacac atcatcaggg cctaattttt gcaaattgtt gtctccctgt 93120 gagctatcac ctatccttga ggaagatgct tctgagtctt cttccatagc agcagcagaa 93180 catgcagctt tttccttttc atcttcatct ttgtcttcat cttttgcttg aagagatttc 93240 agttcttcct tggtgtgttg tttaactttc cggaagctct gtaccaatgc ctcagcacta 93300 gaaaaaactc ttccaataac acggattaaa ggggaataat cctctctttc tctacataat 93360 tcaagaattt catatacctt ctcttctgtt aagtaagtca catctagaaa atcagaggaa 93420 aaaagagaac atttattttc ataatatgta tgtttactct gttgcaaaaa gttctaaaag 93480 taaaacagcc aaacattcta ggctcaatat catttatgat atacaactct taaagtatct 93540 aatacttaga ttcagcaaac aaaatttaat gcttacctat ttttttcaat gaactaccta 93600 cctataccaa tgacctcacc catgctttta cattctttca acaatgtata actcttaata 93660 agatcatgag tttaaacttt ctttataatc aagatatcta ttaatgtata gctttaatta 93720 taaatatgaa ccaatatgtc atgtactgat taatcataat acagctctta aaacctcact 93780 gtagaacaca cagaaatact actaatctgt gagttttctt gtttcagtac tctgttctcc 93840 aaagactaag aaggcaaggt cttaaaaaaa ggctccttca gcatctatgt atgtattaaa 93900 atcaaactgg ttcattttgg gtcttcctag tttgttccag ggtagtcatt ctgtgagtga 93960 ttgagaagaa tataccattt ctcatcggct cttaagtaga aactgctttc cacagccagg 94020 aatcaggtta gactaaatct catagagtga cagaaaatag tttttgagca atgaaaacaa 94080 acagtgcaaa gaagtaaact tatgagctgg caagcagtgc agagactatg tagtcatcaa 94140 aatctatttc ctcttttcct gggcacagag ttggaccaca tttcccaact ttttgagata 94200 agtgttattt tcaggccaag gctttctccc ttctggctaa taggatgaaa gatatttcat 94260 ttcacaggta aaaacaaatg atatattttg tgtactgacc aacataatac tgagaatagt 94320 cttaattctc ccttttatca ataaagtgac atacttgtca tcatcagatt aactacttga 94380 gaggttaatt ttagaggcac acagacaatc ctacctccat tgcgccaaat atacccttat 94440 acatgtagtg tacaacatgt agaattttta atgactccca cctctgctat aatatatgtt 94500 tcacaatgaa agacaatata aaatgtaagt gatcattgaa tggtctccaa aaattgaagc 94560 acaaaaatac caaattttat catactaagg atctgatctg tggcccagct acaagagtac 94620 caacacttac agtttctttt atgggcctta actctttaag aactaattct caggtttgtt 94680 ctattaagaa tatataagca tcttttgcta aacatcagta acctcttccc caaaagcata 94740 aaaccactgg aaacctattt ctcattattt tcattgaaaa tttttaaaat accttcttac 94800 aagacaatgc aaaactccta atttcctaaa atgtaacata acagaaaata ctactatcct 94860 attaggacat gaaacacttt gcttcctgag caagtcataa ggttaacaaa gacttgcttt 94920 gcatgcagta atatggcctg tcctagggat caccattcta gactcacatg tcctttgttg 94980 atatgtcatg ctttcggaac atcttcaagt gattctgaca gtctactaat cctatataga 95040 atgtacctat actttttcca aggagtgttt tttgttgttg ttttttgaca tggagtctca 95100 ctctgttgcc aggttggaat gcagtggcac catttcggct cactgcaact tctgcctccc 95160 gggttcaaac gattctccta cctcagcctc ccaagtagct gggactacag atgcacgcca 95220 ccacaactgg ctaatttttt tgtattttta gtagagaggg ggtttcacca cgttggccag 95280 gttggtctcg atctcttgac gtcgtgattc gcccgcctca gcctcccaaa gtgctgggat 95340 tacaggcgtg agccactgtg cctggcctgt agtgtttaat atgttaaact gaatttttca 95400 ggtatataga taaaaattag tcaaaaaaca ctgtaattag atatgaacat tcaaaaagtt 95460 tggtttattg atacaggtgt tctactgaga aagacatttt tataagattt cttgtgataa 95520 atgtgtccct gaaaatactc aatcttttaa attttgcact taaaaacctc ctacgcaaaa 95580 acagtttggt gcagactact taatacttat gcaactttgt aattagtgtt aacaaacata 95640 attaataatc aaaataagag tactagtgta cagaaagcat ctctaatttc caatatacaa 95700 tagtaactat agaacaatgc aaaaacaaaa acaaaaaaac cagtaacgaa cagggaacag 95760 taacagtagc atattagaaa acagggataa ggaaaggtca caactgctat aatgcagact 95820 tgagcaaaaa gaggaggggg cataaagact ggataaagcc acacaataag cacctctaag 95880 atggagcacg tggccaaaag agcagatgag cacattcctc atgtaccaca tcccccgcag 95940 ctggctgcat tccactgtgc cagcactcta cattcagtta ctggtactct ctggtgcaca 96000 cttactggag aactgtgtac aataaagtca atgcagcttc cacattatac tgacacacta 96060 tatatacaga caacatttac ctattttccc atagtgtgtg aactaattca tgaaacagaa 96120 ttatacactc tgaagcaaca aagttgtgta aagtgacgaa aataatttta ttgtggaaac 96180 agagtagagg ttataacaca atgccacttc actaattctt tcaaacttga ttcaaatgat 96240 gttagtgaaa gttttagagg caaatgcctc taaaattctc tgacttgtat gtcataaaaa 96300 aaaagctttc tctcttaaaa tacaattgcc tctgggtgtg tgtaggggtg agagtggagg 96360 ggcgctaagc cctggtagtc attcaaaaat ttgattactt tgttactaat taccttcact 96420 gaagaaaata acttggagtt ttagtattag cgacaaggta atcgaattct gaattttgga 96480 cgtaggacca tttagaaaac aaaagacctg agtgaagact gtcattggta ggtcatgatc 96540 cttggcagca tgactgtacc aaatgtccgg aaggagagtg agaagcatat atctgaagga 96600 aacgtagaat tctcacataa ctatcacaaa attttgtctt gccttcaaaa atggaaaaaa 96660 cccactgttt cctctttctg cttctttcat cacatcatcc tgaggttcca gaactcatgc 96720 cagatactta gtccagttat tctataactt aaatagatgt tgtggcctag ttttggagat 96780 tcactaccac ttaatacatt tttcctaaga attttaaaaa gttcaaatca atctattaac 96840 aaatgaactt ttggcatatg atctgcttct aattagcaat gattagacct gtaaaatgta 96900 gttattattc ctgtccgtta ccacaataaa aaattggttc tacgatatca aaatgtcttt 96960 atgtcacaga agaaaaaaca aataaaaact aatacattta aatctcccac atggttttca 97020 ggcaacaatt ctcaattgaa aataaaacat cttaccttta aaatcaattc tagcgccttt 97080 cttgttcatt tttatctcag agcaggagtt gttgggggca cctttcgagt tctcaaggta 97140 agctgagctt gctcctttct tggagggatg aggatcacag agttttgcat taatcttata 97200 aagctcgagg gctttaatag ctgctgcatt attatccata cgaagaaaag ttggacagga 97260 agcacaaaac tcattcgtgc aggcttcatt tccacagccc tcagttaact ggtggtagta 97320 gcgttctatt agatgctttg cagctgctcg cttcctgtac caaacattca aacaataagc 97380 acagtgatta gtacagctct caagtacaaa gctcaacata tcatcaaggc aaaagttagt 97440 caagcactga agtgattaac ctgtgtatga agatgagaag tagaaaatgg agatgcacta 97500 tttaccacaa ctcctgacta gtgaaatagt taataaatat tttctaggat attatgataa 97560 agaatgtcaa tgcttactga ctgtattaac agagtataca ttcctttggt ttaaaagggg 97620 ggaggggggc ttgtctgatg gtatatgtgc ttaagttgtt tagtacaaca gctgaaaaat 97680 cacaaggttt acagctaaga gttgtaggat tctatcattt taaaaattag cattaggaaa 97740 atgagtctat ttaaagcatc aatccggttt tcttttacat aatcagtatt tcatttttaa 97800 cagcttgtaa acatttgact tatagttaac acagaatatc tatctggaat aaaaactatt 97860 tttcccaatt atcaacaaca tgggagactt aaaaataaat ttgtaagtgg aatatccaaa 97920 gatagtgtta cactgaaaga aagcggctgc agcctgagtg aggcagatca tgactgtaat 97980 caatcccata actgtgggag gctgaggcag gccgactact tgagcccagg aggtcaacac 98040 cagcctgggc aacatagtga ggctactctc tacaaacttt tttaaaaaaa attagccaag 98100 tgtggtggca tgcacctgta gtcccagcta cttgggaggc tgaggatcac ttgagcctga 98160 gagtcaaggc tgccataagc tgaaattgca ccactgcact ccagcctggg caacagagct 98220 agactttgtc tcaaaaacaa acaaacaaac aaaaaccaaa aagaaaaaga aaaagaggct 98280 ccaaagtgta gaatcttaaa tctaaaactt gtcactaaac ctcctcatta gttccacgtc 98340 acaagatgga atattttaag ttccatcacg tgaaatctta tattcctttt actctgtcaa 98400 cttaaagtac acagattaat gtcctattat ggctgtttca ggagagctac caaaactgag 98460 ggaggaatta tgtgaccatg taagaagtta gatgacatta tattcaacac taaagagtct 98520 atgcttctac taactgataa aattaccata atttcagtag aataaactac tggatccaaa 98580 gaaacataag tcatagccat tccttttggt cccaaattca caagcatgga aataacaact 98640 acaaagaatc aaaattataa gaaaaatagt tcagctgatt ttcaaaacat tcacagaatt 98700 atctaacatg taggactaga tgaccaatgc cagagtttac atcttgctaa tcatgagaaa 98760 ctcaacaatt aacaaggcag caagtaagtg aagaaacaca cgagatccaa ttttgtctca 98820 acagaagaac tttcactctc tgtccaggta ggtgacaaaa agtgataatt cacacacatt 98880 caattcattc tggtgcttat ttttcaaatg ttccatgcaa atttaccact cactgcatgc 98940 aaacagagaa aaaagaaaac ccacaaagca catgtaaaaa ttgcataaac atgacttaaa 99000 gacattttgc tatctatgaa gctataaacc ccacctgaaa attaaaaact gttatcacag 99060 atttagcact atgcaaaata tgaaagtgaa aacatgtaaa aataaaatgg aaatgcagaa 99120 tctagaaaat ttaaaatata tattgctacc cttcagtaaa gaaagggaga taatgtcatg 99180 ttctcccaaa ctacagtgac ttccctggtg aaaatgtaag taggtatttc ctttctggag 99240 gaaaacagtg aacatgtatc gaaagtctta aaaacacgaa taccgtgtga atgagatcct 99300 acttgtggaa aataatttga caattttaca aaaatgcatt gtttctatat ctgaaaaaaa 99360 catgtctaat aaaagattac ttaaatgaac tgataatagg tcacacaata aaataaaaac 99420 tatcaagatt tgaattcgac aaagaactgc ctagtcttcc tgatatatca ctaactgaca 99480 aaagtcagtt aaaaagtagc aggtgtagga tgaacccatt gttatttcaa agcattaata 99540 gcattttctc tggatgatgt gattaagtga gttttaaaac ttcttccatc ttttgatttc 99600 ttatttattc tttccatagt aaggatgcta cttgcatatt aaaaattaat aactataagg 99660 ggaaaacaat agcagttata aaacttcata tacatgattt gaatggcccc gagatttact 99720 aaattgtctc tgatttttaa aaaaattaca aaagtcaaaa taccaaaata gatattttta 99780 atgtgagctt ttatactaaa ataacctccc caaaacttgt cagatacata gtacttcttt 99840 atatactaca taggaggaga gtgatcagca caaacagaac gagactgaaa aatcagaaga 99900 tctgcattaa gtgtcatcct tctgtcccta agcagctgta ggatcctagg gaaacaattg 99960 tctgggcctc agttttccca gctttatgag tcccttcagt tctaatttta aagttatttt 100020 atgtaatagg gaggtgagca agaaactagt atttgctgga tgcctgataa cttattacac 100080 acactgcggg gcactttgac atgggttatc tcatttgaat accatgacat tgaggattat 100140 cttcagtcca cagccaaaga gagaaataga actggagtca aatcacgaaa ccaagatctc 100200 aaagaaagta cagaaccaag acaagaatag gagtccagga gtctttcagc ttcagagtct 100260 aagtcatttt gactatattg ttttgcagaa ggtgattcat ttcaaaataa ttatttttta 100320 acatgagtaa tactgaagaa ttctatggaa aaaaatctca taactaatgt gcaactggga 100380 aaaaaatctg aagaatcata acgtgaacct cacatttatg catctatctg gtaccacaaa 100440 ggcagaccaa gtttcttgag gaaatggaac cactatattc tgcaaagtta atttctctct 100500 aatttgttga ggacctatgt gctatgcatt ttatagacat tcccacttta gaggggaata 100560 aaccttaaca gttaagagct cgcattctga ggccagatgc ccaagttcac ataatggctc 100620 tacctcttaa ttaactatgt gaccctgaat gaattacttg atctttctgg acgtaagttt 100680 cctcgtaatt taaatggtag tatctacgag cattatcatg gtgagagtat tattcttctt 100740 cacattacca attgtgagaa aattaaatgt gttaatatat ataaagtgct tagaacattg 100800 cctggcacat actaagcact atgaaagtgt tagctactac tattattgtt gtaattgtta 100860 ctatcaccct cacaagtgta tgagttagca ctataaacct tcattctgct gatgctcaga 100920 gaaattacat aagtcataca tctaataaga gatttgaact cagctactaa acttgagctt 100980 ttaataacta ttaagaggag gatctgaaag tagccctcta tatttgatct gcctttctgt 101040 gccaagttta acaaatagca gctacactga tgagacagga ctaaaggaag ccatgccaga 101100 acctccaagt taatggtgga atcaactata ttaagcattc ttcttttttc ctcactccaa 101160 tgacacctta atttatctga cctcatctgc atcactatct aatttaggat atgtaaaagg 101220 catacaaaat ttagagcaca taaaagggcc tctacgttgg aaaagtatac actaataacg 101280 actttttggt atagttcctg cgcaagggaa atccttgtac catatgggtc accaaatcat 101340 agctcgtaag tcaaatcgag tccaccacct gtttatgtct ctcaagctta gaatatttta 101400 catttttaaa tggctggaaa aagtttgaaa aataataata gtttgtaacg tgaaaattat 101460 aagaaattca agttccagta tccatcaagt gtactggaac atacccaagt tcattgattt 101520 ataaatatac tatatatgat aatgctttgg ctctgtgtcc ccacccaaat ctcatcttga 101580 attgtactcc cataattctc atgtgttgta ggagtgaccc cctgggagat aatctgaatc 101640 atgggggcag tttcccacat gctgttcttg tggtagtaag tctcacgaga tctgatggtt 101700 ttatcagggg tttccgcttt tgcatccttc tcattttctc ttgtcactgc catgcaagaa 101760 gtgtctttca cctttcgcca tgattctgaa gccttcccag ccatgtggaa gtgtaagtcc 101820 aattaaactt cttttttttt tcccagtctc aggtacgtct ttatcagcag cgtgaaaaag 101880 gactaataca atatactata tagtttatgg ctgtttttca tactacaatg gcagagttga 101940 gtactttagg cctgcaaaac ctaaaacaaa taccacctgc cctttacaga aaatgtttgc 102000 caacccttag tttaggatct attatttatc tctgccctcc agtgaccctg ccatctaatc 102060 atttggcctc ttaactctct ctttaccctg agcaaatccg taaaataaaa ggtatacctt 102120 tccccaagta ctattaaaga aaagaagagg agaggggaaa agggaaaaag gggaaaagaa 102180 agtgaggaaa gggagaggat gcaaaagaaa aagaaggaaa gaaaggaatt tccctgatga 102240 gatcccttag taatacctta tcagctgttc ataatcaaaa ttcctagaag aggaacaaca 102300 gcttacttgc tataatttct tcacattcca ttgacttttc ttattactca aaaaacaaag 102360 tatgttataa tgtgttgatt tttaaaataa aacaaacttt tcttatttag tcagcaatga 102420 aggtcaagtg agaccttcta gtaaaagtcc tctaaagtca gacacatgaa aatacttatc 102480 catttaaaac agacaatact ttccaattat ttatttctat gattgaatta atgggacagt 102540 gctacaaaca gaagtcctat ggaataagtc atacttggaa gatcagagtt tactctagac 102600 aacttgacag caatcagttt aaaaatggtt tcacctagag ggatgtgtac taatgttagc 102660 aattaacttt gaaaggcata aaaattaaga tggattgatg gatacaagga tggttatacg 102720 ataaagcaat gtaagtatta atggcagaat ctaggtggca ggcatatgtg tgtcagctgt 102780 aaaatttgtg ttcaatgttt ttttagttcc cacatatcag tgagaacatg tgatatctgt 102840 ctttccgtgt ctggcttagt tcactaaaaa aatgaattta caagacaact ggaatataag 102900 caatgaatac aagcactaag aagatgaagc catagaaaca gctgccagaa agtgaagatg 102960 tgacagtgaa cgccaaacaa gtaagattag aattacaatt agaatcagaa atgacaaaaa 103020 agaaacatga actgtgagat gcaatataaa aactaatggt gaacaaagca aagaataaaa 103080 aataaaaacg gaaagattaa aaggaaaatg tgactgtaag tagagtgacc tttatattat 103140 acagaaggta aagcagaatg aacatgtgag gaatctaaaa aacagatata aaatagaaac 103200 aactgaaggc ttatataatt agtctataaa gctaggaacc actgcttagt aatttctcgt 103260 aagtggagtc tctttgttct gagacgttgc aaaactccat tccatctcaa agttattttt 103320 aatgttaaaa tttgtaagag tgagcaacgg tatcctaaat agttctaggc cttgtagaaa 103380 tagactgtaa gagacatctg tgacacaact atattcagta tgatgtaggg tctgttacaa 103440 tgggatgaag tgaatttaga ttatttcaag actaaaccta caattgtgaa ctcattagta 103500 ccatgaaccg aacaaaaacc tattaaatat agaacaagac gattttcatg aaaaaataaa 103560 tatgaacaaa tcagtatttt cagttgtttg aaatataggt taaccttcaa ttactgtttt 103620 atggccgggt gcagtggctc acgccacgcc tctaatccca gcactttggg aggccgaggc 103680 aggcggatca tgaggtcagg agatcgagac catcctggct aacatggtga aactacgtcc 103740 ctactaaaaa tacaaaaaaa aattagctgg gcgccgtggt gggcgcctat agtcccagct 103800 acttgggagg ctgatgcaga agaatggcat gaacccggga ggcggagctt gcagtgagcc 103860 gagacagagc cactgcactg tggcctgggc aaaagagcga gactctgtct caaaaaaaaa 103920 aaagaaaaga aaagaactgt ttttttcatt tttatagtct caatatccag aatgcgtgat 103980 atatgataaa aaaaaaagta aaattgtaga actaaatatt tacataattc atctgtaaaa 104040 tgaaaatctg ttttacagtg tcatatttca cagttagaaa ggaagaaaaa ccttaaatca 104100 acaaattaac tttacatctt atggaattag gaaatgaaga acaaatgaga ctcaaactta 104160 ccaaaaaata aaaaaaataa aaataaatta cagctaaaat aaaatagaga aaaatagaaa 104220 atttttgcaa tagaaaaaaa atcaacaaaa ttaggagtag ctgttttatt gaaaagatca 104280 acaaaactgg caaattctta gattaagaaa tgaagagaat agacacaaac agcaacaact 104340 ggaaattaga aaggcgatac aacaactgct gccacagaaa taaataggac cttaaaagac 104400 taatatgaac aactatgacc caaaaaaatt tgataacctt tgagaacgga tagacacatc 104460 aaacccacca agactgagcc acaaatacat acaacttctg aatggaccta taactattag 104520 agattgaatc agtaactgtc caacaacgcc agggcttcac tgaaaactct accaaacatt 104580 taaaaactaa caacccttct caaactcttt gaaaaaacta gaggacagaa cactttcaaa 104640 atcattttat gaggtaagca ttacttagat atcgaaatca gacaaattta caagaaaaaa 104700 gaatccctaa taaatactga tgcaaaaaaa atcaacaaaa taccaagaaa cagaattcaa 104760 caatgcatta aaaagattat atttcataaa ttctcaactg gaatttattc ataaaatcca 104820 aggatggttc aacatacaaa aaaatcactt taatacactg cattcttagg acaaaaacca 104880 ataatctcaa ctgactcaga agaagcattt gacaaaaatc aacacccttt taggatttaa 104940 aaaaaggcca gacagggtgg ctcatgcctg taatcccagc actttagaag ggcaaggtgg 105000 gtggatcacc tgaggtcagg agtgtgagac cagcctggcc aacacagtga aaccctgtct 105060 ctactaaaaa tacaaaaact aatcgggcat ggtggtgggc gcctgtaatt ccagctactc 105120 gggaggctga ggcaggacaa tcacttgaga acccgggagg cggagctggc agtgaggtga 105180 gatagcatca ttgcactcca gcctgggtga caagagcaag attctgtctc aaaaaaacaa 105240 aaacaaaaac gctcaattcg ctagaaagat atggaaatta cttcaacata atgaaggcca 105300 tatatagaaa gaccacagct aatgttattc aatgatgaaa aactgaaagt tttccctcta 105360 agatcacaaa tggaacaaga atgcacacat tcaccacttc tattcaacat actgttagac 105420 atcctgccag agttagcaac tgggcaagaa aaagaaatga aaggtattaa atgagaaaag 105480 taagaagtaa aattacttct gttagcaaat gacatgatct tttatgttga aaactctagc 105540 ctaccaaaaa gaaaaaaaac cgttagaata aaggaattca gtaaagttac aggatataaa 105600 aaccaatatt aagaaaagag ttgcatttct aaatactaaa aatgaagaat ccaaaaagga 105660 aattaatttt ttaaacccat ttaaaatgaa atcaaagagt aaaaaatact tagggaatat 105720 tttcaccaag caaatgaaag acatgtacat tgaaaattaa acaacatagg ccggacgtgg 105780 tggctcacgc ctgtaacccc agcagtttgg gaggccaagg tgggctgatc acgaggtcaa 105840 gagattgaga ccatcctggc caacatggtg aaaccctgtc tctactaaaa atacaaaata 105900 aattagctgg gcttggtggc gcgcgcctgt aatcccagcc actcgggagg ctgaggcagg 105960 agttgtcact tgaatttggg aggcagaggt gcagtgagcc aagatcacgc cactctactc 106020 cagcctggtg acagagtgag actctgtctc aaaaaaaaaa aaaaaagaaa aagaaaatta 106080 tacaacaatg ctgaaagaaa ttaaagacaa tacaaataaa tggaaagaca tccaagttta 106140 tgaattggaa gatttagtac tgttaagatg gcaatactac ccaaagcaat ctgcaaattc 106200 aaagcaatcc ctatcaaaat cccaatggca ttttctacag aaacagaaaa aaaaaatctt 106260 aaaattaata cagaatcttg aaggaccctg aatagccgta acaatctgga caaaaaacaa 106320 agctagaggc ctcacattcc ctgatttcta aagatattgc aaagctatag taatcaaaac 106380 actatggtgc tggcataaag acagatatac agaccaagtg agcagaagag agaacacaga 106440 aatagggaaa agaggttctt caacaaactg tattgggaaa tctggaatct aacatgcaaa 106500 agaatgaagt tggagcctta tctcacacca tatacaaaga tgaactcaag ctggattaca 106560 gacctaaact taaaacatcg aattataaaa ctactacaag aaaacatgga gaaaaagctt 106620 catgacattg gacttggcaa tgatttcttg aatagatcac caaaagcaca agcaaccaaa 106680 gcaaaaatag acaaactggg gatacataaa ctcaaaaatt tctacaaagc aaacagtaaa 106740 tggagtaaaa tggcaaccta caaaacagga gaaaatattt ctataccatg tatctgttat 106800 ttggttaata tccagaatat ataaataact cctacaattc aacaacaaaa aatctagtta 106860 aaaagtggac aaaggacttg aatagtcatt tttccaaaga atatatacaa atgggcaata 106920 agcccatgaa aagattctca ccatcactga tcagtaggga gaaatgtcaa ttaaaactgc 106980 aatgatacat catctgaaac cattaggatg gccaccatta aaaaaacaga aaataagtat 107040 tggtgaagat atggagaaac tggaaccctt atgcaccact ggtgaaaatg taaaatggtg 107100 ccaggcactg tggaaaacaa catgaaggtc cctcaaaaaa tttgaaatag aattacctcc 107160 agttccacat atgaagagct tggaagtcac cactccatcc taacaacaag taaaaaatga 107220 caaacttaaa aataaacaaa tctgagatag gataagtgag gtcacagggc aaatgactgc 107280 ctgtgagagc agagaacagg tgaacacata gcatcaccat ttatctgaga tgaaaaacac 107340 aagcagaaac ctccacgggg taggaaatcc tgaagtgtaa tagacaaatt gatgaaggct 107400 cagtgtggac aactctgaaa gctaaaaact ccagagttac ccaattatag ggggagccct 107460 acaattttct aagttttaca tccaggcaat tgaccagctt ctcacagtaa atataggaga 107520 aaaatcctca accctcagca ggggaggcaa agagaaatga ttttcaagta cactagacta 107580 ttccagtctt aacaaggttt gtcctcagga gaaactagtt aaccagagcc taacctgctg 107640 gggttgtagc aaagccaaaa tgatgtgggg gaagagaaat aacccaactt caggccatta 107700 tagctatctt gttctaacta agggaatgag ggaggggtgg gattgagaaa cacttgtgaa 107760 gttcacagtc cagaggcata agctcactaa aaagactgac ctaatcataa gactacagaa 107820 ctcttctcct ctccctacac cttacaacca cattactaaa tgctcattta caacagttcc 107880 ttttacctag tacatcatgt ccaagctatc aagaaaaaaa ttacagggca taataaaagg 107940 taaaaaacaa gcaccaggac cagatacagc agggatttgg aattatcaaa cttggaatct 108000 aaaacaacta tgattaatat gctaagggcc ctaacgaact gagtaaacaa catgttaaaa 108060 aagtagagat gaaaatccta agaaccaaaa ggaagtgcta gagataaaac acaaacaaaa 108120 acaaaaaaca gaacactgta agagaaatga agaatgcctt tgatgggctt attagtaggc 108180 tgggcatgga tgaagaatct ctgagcttga aaatatgcca aaaaactaca tctgggcata 108240 aaacgttgta attacagaaa ttcaaggata agaaaaaaat ccgaagtaag ccagagggaa 108300 aaaatcacct tacctgtaga ggaaaaaaag aaaaaaaaga aaaaatacat gtgacttcca 108360 acaagaaaaa gagtgaaata ttcatagtgt tgagagaaaa aaaaaccata aacctagcac 108420 tctaccttgt gagattatta ttcaaaagtt aaaaagaaac actttctcag acaaaaatta 108480 aggaaatttg ttgtcagtac acctgccttg caataagtgt tgggaagttc agaaactgaa 108540 atctacatat atagagcatc aaaagaagga aacactgaaa gtaaaataaa accttttatt 108600 tttcttatac ttaattgatc taacaaataa gaatttgttc aaaataatgt caacaattgt 108660 gcttatgcat acaaatgctc ctaaacttac ttattgggtt gtgtcccaat accattataa 108720 attgaaaata tcatgaaaac acaacttatc caaatttgtg ggatacagtg aaagcagcgc 108780 ttagaaagaa acatacaaca ctgatgcatt tattagaaaa gaattatcta ggccgggcgc 108840 tgtggctcac gcctgtaatc ccagcacttt gggaggctga ggcgggtgga tcacatggtc 108900 aggagatcaa gaccatcctg gctaacacag tgaaaccccg tctctactaa aaatacaaaa 108960 aaattagcca cacgtggtgg caggcgcctg tagtcccagc tacttgggag gctgaggcaa 109020 gagaatggcg tgaacccggg aggcggagct tgcggtgagc cgagatcgag ccactgcact 109080 ccagcctggg cgacaaagcg agactccatc tcaaaaaaaa aagaaaagaa aagaatgatc 109140 taaaaatcaa ttatctgagc taccaactta tgaaactaga aaaagcaaat taaatccaaa 109200 tagaagtaat aaaaattaga gcagaaatca atgaaattga aaacaagata tcaatagaga 109260 aaaatcaaag aaatcaacta gttctctgaa aagatcaata aaatcaataa gcctctagcc 109320 aggctaagaa aaagagacaa aggacaaaat aactaatatc agaatgaaaa gagtggacat 109380 cattacagat ctcatggaca ttaaaaggat aatcaaggga tattatgaac aactttacgg 109440 ccacgaattt ggtaacctag atgaaatgaa tcaattcctt aaaagacaca atctattaga 109500 actctaagaa gaaataatct tgattaaaaa gcatatatta aagaaattaa atccataatt 109560 aataatgttc taaaagagaa ggcatcaggc ccagatggat tctctgatga attctactaa 109620 acatttaagg aagaaaccac accagttctc tacaatctcc ttcagaagac agaagcaaag 109680 gagatgctcc tatctcattg tatgaagtca gcattactct aatacccaaa ccagacaaag 109740 acattatcag aaaagaaaac tacagaccca tatttgtcat gaacaaagat gcaaaaatct 109800 ttgtattagc aaagtattag caaactaaat tttactacaa tgtataaaaa gaagtataca 109860 ccagcacaaa gtaggattta tcccaggtat gcaagactgg ttcaatattg gaaaatcaat 109920 taatgcaatt caccatatca acagactaaa gaagaaaaat cacatgacca taccatagat 109980 ggagagaagt atgtgacaaa atttaacacc cactcatgat agaaactagt aaactaggaa 110040 tagagggaac accttcaact tgataaagaa cgtttacaaa aaacatacag ctaacaccat 110100 ccttaatgat gagaaactag aaactttctt actaagatca ggaacaagaa aagaatatcc 110160 ccacctcacc actccatact ggaagtccta gctaagacaa gaaaaggaaa taaagggtat 110220 actaacgggg aacaaaaaaa tacaactgcc tttgtttgca gatgaaatga ctatatgtgt 110280 agaacataga caggaattga aaaaaagaaa aagaaaaaca acaaaaacct cctagaacta 110340 ataagtgatt atagcaaagc tgcaggatac aaggttcata taaaaaagtt aatagctttc 110400 ctgtaaacca gcaatgcata agttgaattt gaaattaaaa acacaatacc attttacatt 110460 agcgtgtccc aaaatgaaat atttaagtac agatctaaca aaattagtac aagatatatg 110520 aggaaaaatg ttttagaact ctgatgaaag aaatcaaata actaaataat gaagagctat 110580 tccatgaccc gtgagagaca actcaatatt gacagaaaaa gtcagatgga cactactgat 110640 ttcaagattt actgtaaagc tacagtagtc aagatggtgt ggtactgaca aaagaactga 110700 caaaacagac caacgaaaca gaatagagag cccagaaatg gacccacata gtcaaaggag 110760 caatggcagt atttgacaaa gaggcaaagg caatacaatg aagaaaatag tctttttcaa 110820 taaacagtgg taataactga acatccacat gcaaaaaaaa aaagagtcta gacacaggtc 110880 ttacaccctt cacaaaaata aactcaaaat aaaccagaga attaaatgta aaactcaaaa 110940 ctataaaact cctagaggat aacataagaa aaaatctaga tcttgggttt ggtgatgact 111000 tttagatacg gcaccaaagg taccaaccat gaagaaaaga actgataagc cagacttcat 111060 taaaattgtc tacttgtttc ttaaaaattg ttgtcttttg caaaagacaa tgtcaagagt 111120 atgaaaagac aagccacaga tagggaggaa atatttacat aagacacatc tgataaagaa 111180 ctattaacta aaatgtgtaa ggaggctggg tgtggtggct cacatcccag cactttggga 111240 ggccaaggtg ggtggatcac ctgaggtcag gaggtcgaga ccagcctggc taacatagtg 111300 aaaccccgtg tctactaaaa atacaaaaat tagccaggtg tggtggtgca cgggtataat 111360 cccagctact cgggaggctg acgcaggaga atcacttgaa cccaggtggc agaggttgca 111420 gggagccaag actgtgccac tgtactgcaa cctgggtgac agagcgaggc tctgtctcaa 111480 cagacagaca gacagacaga caagacagac agagacagtg taaggaactc ttaaaattcc 111540 acaagaaaac aaacaaccca attaaaaaat tggccaacaa ccttaacaga cacctcacca 111600 aagatataca gatggcaatt cagcatatga aaagatgtcc cacacatcat atggcatcag 111660 agaaacacaa attaaaatta taagatacct ctacacacct atcagaatgg acaaaattca 111720 gaacactgat aacaccaaat actggtgaag atgtagagca aaagaaacac tcactcattg 111780 ctggtgaaaa atgtaaaagg atagcgtcat attagaagac agtttggatg tttcctacaa 111840 aactaaacac ttttaccata agatccagca attgcactcc ctagtattta cagaaagtcg 111900 ctgaaaacct aagtccacac aaaaacctgc acaccgatat ctacagcagt tttattcata 111960 attagcaaaa tgtggaagca accacaatgt ccttcattag gtgaatattc attcacaaac 112020 tgtgatatgt ccagaaaatg gaaaaagaga ggtactaaca acctatgaaa agacatggaa 112080 gaaactttaa tgcatattag taagtaaaaa tagtcaagct gaaagggcta tatactgtat 112140 gattacaagt atataatatg ctggaaaagg caaagttaga gacacagtaa aaggatcggt 112200 gattgccaag gagtgggagg gaaggaaaga taaataggca gaacacagag gattttgggg 112260 cagtgaaaac attctgtatg atataatggt agatacatgt cattgtactt tgttcaaagc 112320 cacagaacgt acagcactaa gaatgatccc taatataaac tacggacttt gggtaattat 112380 gatgtatcaa tataggttca tcagaaagac atgtaccact ctggtgggag atgcacactg 112440 gctatgagag aatccataca tgtgtgtgga aggaggtaca ggggaaatct ctgtaccttc 112500 ctctcaattc tgtgaaccta gaactcctgt aaaaaaaaaa aaaatctaaa aaaaaataga 112560 atacatatga tccagtaatc ctacacctgg gtatacttcc aaatatatta aaaacaggtt 112620 ctcaaaaaaa tatttgtata cccatgttta tttcaacatt acaatattca agaagtggaa 112680 ggaacctaaa catccatcaa caaatggtta aagaaaatgt ggtatacata tataacaaaa 112740 tgttattcag cctaaaagaa aagaaagaaa ttctgtaata tgctacaaca caaatgaacc 112800 ttgaggacat tgctatgtga aataggccag tcaacaaaag acaaatactt aatgattcca 112860 ctgacatgaa gtagccaaaa cagtcaaatt ttagaggcaa aaagtagaat ggcatttgcc 112920 aaggaatagg aagaaggggg aaaagaagag ttgttcaatg aatgtagagt ttctgtttta 112980 caagatgaaa aagttctaga gatctgctgc acaacaatgt gcacagttac cacaattgta 113040 ccgtacactt caaatcatta atatggtaaa atgtgttgtt tttgacaatt tttaaaactc 113100 taccccattg ttttctttac ctcttatata aactgataaa aacctgtttt atcttaatca 113160 attattgtat gactactgct ccccagagaa aaaagtgcat gtgaaatact actacttatc 113220 catctcctgg ctctgagcag tacatgtcag gaacaagagg gaattgtagc tggaagacag 113280 tagaagagcc ataggacaag tctctaagag aaggaagaaa aggcgcaatg aaagaaaaca 113340 agtttaagat agtagaaaag cattcaaaga cggcaacctg aggtaaggtg ttttcactga 113400 agcttttggg gtaaaacagt tttgagttgg catgcctgta gacatgggaa gcagcagtga 113460 tgcagaggtg aacattactg tagataaaaa cggatgggaa tttgacttgc tagggactga 113520 ggggttaatc atataaataa agatggcagc agatttggga aagagtgaag aagaataagt 113580 tcaggtagca gtcctcaaaa accgagaaga aactgatagc tcactgaagg cagacagagg 113640 aagacaaaac cagaaggcat aagcttcaaa ggagcaggga tttttatgct gagagagtaa 113700 aaggaatagt tcaaagcagc agtggagaac acgaataacg ttccatgtgg gaaaagaaca 113760 tgtccagagc ttactgtacc tataacctag cttctgtaac tggaaatgaa gaatctgctc 113820 tagtcaggtc atcacttttc actacttatt ttacttggcc ttcctaagaa atatagacct 113880 tttggaaatt attgactttt gggtctagga cactatttct tggtttcctc ccttctctct 113940 ggctgttttt cagagacttc ccttccaaat ctagagacat ttgtattctc cagggatcag 114000 ctattagata ctttcccttt taaatttccc tttggacagt ttcatctttc aaggattgag 114060 caataactaa atgacttcca aatgtctact tcagtataaa ttctgcttgt caggctacat 114120 aaaaagggct cttcaaggaa ttatgatgtc taaagaaaga gaaagccacg atttcaatat 114180 cacagagatg actacagagg aatagcaata aaaagagagg caacttagga gaggtgaatc 114240 acaaaagatg actaggagct gatgacacta tgggtgggaa gaatgtttca gacaggggaa 114300 gaatgtttca gatagaggaa aatgagtaaa agcacagggg cctgaaaaca tgatattata 114360 agacaattcc aagcacttca agagcctaaa gttcaagaaa agtttcaaaa atatgaaaat 114420 ggagaggcag ggaaaagcca gatcatggaa gacctcaata gccatgataa gtaattcttt 114480 ttttagccaa aagaggagta atctaataaa agctaaagat cttctcctca taaaaataca 114540 tgcacacttc aggagtgcaa atgcactctt ccggaagatt cgtaacccac tacattcata 114600 aaccattaga taagaactaa aacacaagga gtcactgaag ggttttaagc aggttaagtg 114660 actgacaaaa tttgcctttt caataactga aaccaaagtg ggcaaaactg gaggcaagca 114720 atccagttag gtaatgacta ctgtaatagt ccggacaaat aatgtagcag taggaagaaa 114780 aaaaaagatg aaattgaccc aggaaatatt taaaataagt agtttgtaag aggtaaataa 114840 gctggaagag ccagaggtaa tgggtagggt ttctggtatg ggcaacaaga tatgctacaa 114900 gctgagatgt tagtaaaaac aagcgttcat cagcatttag taagtgattt atttatatta 114960 tatcactgaa tactcaatta tgttaagagg cagacagcag ttaaaaaaca aagaactcgg 115020 tgaatcaaaa agttctgcta atttggggaa atagcatccc ttttattttt gttaatctct 115080 tttgggtttg atcctcattt atagctgaca agaagttcta tgtactaaag gtaaactatt 115140 ctcattaatg ttcccaaaaa tctcttggaa taattaagat ataaagaaat tcaaaattca 115200 catgattata aaaatctttc cttagataat ctcataatat agccatgttt tgctcattct 115260 actttgagaa gattcagcca gaaacagttc atccattcaa ctatccctac tgtgaactag 115320 aagtatgttt ccttacattt gaaacagaag atataggttt atatgatgct tcaggtggta 115380 gaaaagcagg gcagactatg actcgtgtca cttccttcca cacgtgatgc ctttcatggg 115440 ctcctgtgtc tgtcagaaga aagcaaaggg ccttagcgtg ctcctggctt tctatatcca 115500 aatgcatttt ttcacacctt ctcccatcag ctaactctac attactgcaa tacggaactt 115560 cttactactc agtggacttg ttctgctgtc ttctctgatt ccaggtgtta ttcttcctgc 115620 ctagaacact atgattctta gctattccca agcatcctca aggtttcagc ttatatacca 115680 cttttaagat aattaggtat tcttcctctg tagtctcata ccaaccagta cctattctat 115740 tatatataat aactgcctat taattaaatg ggaagctgag gtatatgacc taataactta 115800 tttactgtcg tatcctcaga acctagcaaa ttacagagtc tcaacagaga tttttcaatt 115860 tctcttctga tactgtctcg ataacagtgt caattaaacc tttctctaat tatttgacct 115920 tgaagggaaa tagatgtcag actacctcct ggtttcgagt atactggaag catacaaaag 115980 gaccttctca atctggagac caagaatatg atatgagaac ctataggaga accacttatt 116040 tgattaaaga gatttctttt acttcagaaa atatttcagt atgttacttg acccataaat 116100 gcttatagat gtgtaagtac accgaagaag tcatatagga aataaaagca tccaagctat 116160 atttctatgg tctactctga ttaaaaagct cagctctcct atcaaattca agataatgca 116220 tgtggattat ggagcacagt cacttgctac atggtaaatg ctcaaaaaga tgataggtgg 116280 tattacccac attctacagg ctgtgtacat acttatcagt ttatatatat acataaactg 116340 atcctaaaaa attcttccta catttctgca agataattaa aaaggcagaa acaaacattt 116400 tgcataaatt tactagcttc attctttcat gtaggaagta gttactgact acctactgta 116460 tgccaggcac tgtcattagg cttccattct agtggtaaag aagcaaaaca acaaagaaat 116520 caatatgcaa gaagtcaaat gacattaaat cccatgaaga aaaatgcagc aagttaaggg 116580 gaatgcagaa gaacatgatc attctttgat gcagccggtc aggaaaagca tcatttgagc 116640 agagagctct ctgaatcaag tgaggaagga agccacatgg attatcacag agaagggtca 116700 cagggtcaca gacaatagtt acaagcctta agatgacaaa gatacagcca ttttagacag 116760 agatgagcaa gtgcggtaga gagatcacag aaatgaaagg aagccagttc acacagggcc 116820 atgtaaatct ccagatttta cttttaagat gggaagcctc tgaaaagttc tgtgcatagt 116880 aaataacatg gtttaactca gattttaaaa agatcattcc ggctgctact agagaataca 116940 ctgtaaagca caagactcct gggaaacaat ttctttcttt tgccaaaaga tgatgccttt 117000 aaacagagta aacagaagta taatggttaa aaaaaataaa atgaattatg ggtatttgga 117060 aggtgtagcc aacaagattt accaataatt tgagtatgtg acatagagaa attaaaagat 117120 gcttccaagg cttctggctg cacaggaggg gaaaaaagct gttattgact gagatggcaa 117180 aatattatga gagacgtagg tttgggatga tgaaaatcag gagctccact taggacaggt 117240 taagtttgag aaccagactt aactgttgga taaatcagtc tacagttcag agggcaagag 117300 ctgacgatgg aaatagaaga gttgtcaata gacagagtcc tggggcattt ctgacattta 117360 cagtaaactg agcatttatt aaaactaact tgctttactg aaccataaat cacttgttgt 117420 atttacccct gctccattta tagttataca tctggaaaca tagccttagt gttagaggta 117480 aagagtaaat accaaacata aaaaatctga tctggttggg tgcggtggct caagcctgta 117540 atcccagcgc tctggaaggc cgaggcaggc agatcacgag gtcaggagtt caagaccagc 117600 ctggccaata tggtgaaact ctgtctctac taaaaataca aaattagcca ggcatggtgg 117660 cacatgcctg taatctcagc tactcgggtg gctgaggcag gagaattgct tcatcctggg 117720 aggcaggggt tgcagtgagc caaattgcgc cactgcactc cagcctgggt gacagagcaa 117780 gattccatct caaaaaaaaa atctgaagtt actgagaaac tggtatgaaa tcattaagaa 117840 aactaaggtg tctaaattaa tacatacaaa gagattctac aacacggtat ttataaattt 117900 aaacaaaatc catggccagg cacggtggct cacgtctgta gtcccagcac tttgtgaggc 117960 caaggcagaa ggattacttt ggggccaaga gttcaagacc agcctgggca acatagtgag 118020 accctgtctc tacaaaaaac aaacaaacaa acaaaaacac tgttttagcc tggcatggtg 118080 gcacatgcct gtagtcccag ctactcagga ggctgaggca tgaggatcac ttgagcccag 118140 gaattcaaag ttgtagtgag ctctgatcac accactgcac tctagctgta tcacttatga 118200 cagagcaaga caatatctca aacaacaagc aaacaaaaca aaaaactaaa gtaaatccag 118260 gtaaaataaa catacgaata aatgaaaaga tctgggttat tgcattagtt ctgtttctag 118320 gcttaactac aaaatggtgt ccagttgtta aaaacacttg tttaagagta ttaataattt 118380 ttttttttac tatgctcttc tacatcctag gaaattggca acactaagaa ttcctaaaaa 118440 caaacaggag tgttaactgt atataaatta ttatttaaga tgcattcaag gcgttactta 118500 aaatatcaaa tgcatgtcaa agtacaaaca acaaaatcat gcttcaacaa atgtgggatg 118560 ttgccattaa tggacagtta gctctgaggt aaaaccaaga atccttcatt acctattttt 118620 gtaaattagg acaaatacta ttaaggtatt aggttggtac aaaagtaatt gaacaaacct 118680 ggacccactc acctcactga aagtgctgcc tggctacagt ttctagatat aggaatgtga 118740 gaaatggtag cagccttgaa ggtttagagc tatattccca taccaattat ggctagaaac 118800 ttaaaacagc tctattgaga cattatggga agtctaattt cctgttactc tactttaaca 118860 cagccaagta aaacagtaag aaagcttgct taattcaaca aggactgagt gccagagtgt 118920 cacctggaaa cttgtgacaa ataatcatgc ctcacacatt catccttggt ttttactacc 118980 aaatgcaagc ttcatctatc ctcttccatt ctaaacttga ctcatcctcc taacctcttc 119040 cagaaagatc tctagaaacc cagaggcttt ctgaagaccc ataggctatc ccccatcttc 119100 aactacttta cataatggcc cctcaacttc ttagctttca tgaaagcctg gctcctcccc 119160 aaaggcactg cctatcatgc aaccctttta tgtgactcct aaaactccta agtccaccat 119220 tattcttcta attccctgta ttaaaaataa acggcaaaat tccctgtatt aaaaacaaca 119280 aaaaaacagc ttgtaatttg aaactcatgt catctaaccg aatgccttct ctttccctcc 119340 ctgttctggt caattaaacc cacatattta agcctccact ttgcccccag ttacatcatc 119400 agcaaagtga cttcaatgtc cctgtacatg gttctatccc aatactctag gcccccaaaa 119460 tatttgcctt tctaaatttg agacatcttc acctcctcat ttcagcaaat cactcccttg 119520 tctttgttag acatactaaa acctctgaca atgatcatct cagctatctt tgtaagagtt 119580 tcactcatac tcatatctcc tttcacctgt caagacacca ggtttggtga caaataaaaa 119640 tgatacgtat ttgggaggct gaggcaggag aatcatttga acccaggaag cagaggatgc 119700 agtggccaag atcatgctac tacactccag cctgggtgac aaagcaagac tctgtctcaa 119760 aaaaaaaaaa aaaaaaaaaa aacacaaaaa acaaaaaaaa ggatacatat ttattgtatt 119820 cacatgatgt tccaaaatat gtatacactg tggaatggct agatcaagct aattaataca 119880 tgcaatacct cacatactta tattttatgg cagaacattt aaaatctact ctcagtgatt 119940 tccaaaaata cactgttatt aactagtttc catgttgtac aatagatacc ttgaacaaat 120000 tcctcttaat tgaaattttg tgtcctctga ccaacacctc tgcaacccag tccactcacc 120060 cccagcccct ggtaaccacc attttacatc cctgagttaa gattccacat ttaagagaga 120120 tgtagtattt gcctttctgt ggctggctta ctttcaacaa tgccctccag gttcatccct 120180 gctgtcacaa atgacagcat ttcctccttt ttatggctga agtatattcc actgtgtata 120240 cataccacat tttctttatc catgaacact taggctgatg ctgtatcatg ggtattgcaa 120300 atgataccga aaggaacatg ggagtacaga tctcttcagc gcactgattt tattctttta 120360 tttatatata tatatatata tatatatata tatatatata tatataaaaa tacatatata 120420 tccaagtgtg actgctgaat catatggtag ttctattttt taatttctga gcaaacgtca 120480 tgctattttc cataaatgct gtactaattt acattcctgc catgcgcaat atatctcttg 120540 tctgcaaatc ctcatcatac tttaatagcc attctaatgg ccatttgtat gtcttatttt 120600 gagaaatgtc tattcaagtc ctttgcccat ttcttaagtg aggtgctttc ttactattga 120660 gatgtctgag ttccttatat attttgcata ttaacccctt accagatata tggtttggaa 120720 atactatctt ccattctgtg agttttttca ttctgtagat tttttctttt tgccatgcag 120780 aagcttttta gtttgatgtg atctcattca tcaattttta tttttgttgc ctgtgcttcg 120840 agggggtcat atccaaaaaa atcactgtcc aaaccaatgt catgtacatt tctcctatac 120900 tttattctgg tagttctaca gtttcaggtc ttatatttaa gaccttaatc cattttaact 120960 tgaatttggt atatgatgtg agatacaggt ctgatttcat tctcatgcat gtagatattc 121020 cattttccca acaccaccta ttgaacagac ttccctttcc ccgctgtgtt ctttgcaccc 121080 tgtccaaaat caactgatag tacacgaatt tatttctgtg ctctccattc tgttttgtgg 121140 gtcgatgtgt ctgttttttt gtttcttttg tttttaaaag acagggtctc acgctgtcat 121200 ccaggctgga gtgcagtgat gcaatcacag ttcactgcca ccttaagctc ctgagctcaa 121260 gcaatcctcc ttcttcagcc tctcgggtag ctaggactac agatacacag caccgcgcct 121320 ggctttaaaa attttttttt tttttaattt tagagacagg gtctcactat gttgcccagg 121380 ctgctctcga actcctggtt tcaagtaatc cttctgcctc agtctcccag agtgtgggaa 121440 tacacgtgtg agcaactgtg cctggcctgt ctacttctat gtgactatca tgctgttata 121500 attactgtag ctttgaacta tattttgaaa tcagatagtg tgatgtctcc agctttgttc 121560 ttttcactca tgacagcttt ggctatttag gatcttatgt ggttccatat aaattttagc 121620 actgttttct agttctgtga aatttaacat tggaattttg atcaggattg cattaaaact 121680 gcagattgct ttggataata aaaacatttt acaatattaa ttcttccaat ccataaacac 121740 aagataactt tccattattt gtatcatctt caatttcttt aatcaatgtt acatagtttt 121800 caactctttg gttaaagtta tttctaagta caatcatccc tcggtatctg caggatattg 121860 gttccaggat ctcctgtaga taccaaaatc catggatgct caagtccatt atataaaatg 121920 gtatagtatt tgcatacaac ctacacacat cctcgtgtat actttaaatc attacttagt 121980 acctaataca acgtaaatgc tatgtaaata gttgctatac tgtagtttcc ttattgtata 122040 agaaaacagt atttttattg ttgtattttt ttctcaaata ttttcatcca aatgttggtt 122100 caatttgcaa atgcagaacc actgatactg ggagccactg catgttttgt ttttggtacc 122160 tattatacat ggaattgtct tcttgatttt tcttttagat aatttgtcat taatgtacag 122220 aaattctacg gatttttgta tcttgatttt atatcttaca actttactga atttatcagt 122280 tctaacaatt ctctggtgga gtctttaggt ttttctatat acaagatcat gtcatcttca 122340 aacagggaca acaatgtctt cctttcctac tgggatgcct tttctttctc ttgcctaatt 122400 gctcttgcaa ggacttccgg tactgtgctg aatagaaatg gcaaaagtgg gcattctcgt 122460 tttcttcctg atctcaaaag aaaagctttt aacttttcaa cattcagtat aacgttagca 122520 gtgtgtttgt caatatggcc tttattttat agaggtacat tccttctata cttaattttt 122580 taaaattttg tagcacaaga gaatactgaa ttctgtcaaa tgctttttct caattatctc 122640 aattatctat tgaaatgata acatggtttt ggcctttgtt ctcctaatgt tgtatatcac 122700 attttatgga ttcaggtctg ttggataatc cttgtaccct tgaggtaaat cccatatgat 122760 cacagtaaat gatccttcta atacactgtt gaatttagtt attattttct tcagaatttc 122820 tgcatctaaa ttaagaatac gggtctgtaa ttttcttttc ctggagagtt cttgtctggc 122880 tttggtatct aggtaatgct catctcccaa aatgagtttg aaattactcc ctcttcttaa 122940 atttctcata aaattatgag aacaatctgt actagttctt ctttaaatgt ctgctagaat 123000 tcagcagtaa agtcaccaag tcttgggctt cctttggtgg gagatatttt tatgactgat 123060 acaatccttg tcactggact gttcacattt ttcatttcat gattaagctt ggacaagttg 123120 catgtgtcta ggaatttatc catttcttct atggtaatca atttgttggc atataattgt 123180 tcagtctctt atgatcctct tatttcttgt acttctctgg tatcagctgc aatggttcct 123240 ctttcatttc tgatttaact tgagtcatct ctttttttct tagtctagct aaagacttgt 123300 tgcttttatc atcaaaaaac acaactcttt atttttttta tcttgagtca tctctttttt 123360 ccttagtcta gccaaataac ctgtcttttg agttcagatt cttttgtctg cttgctcaat 123420 tctgctttta atgctctttt gcatttttca ttccatttat tgcattttca gcttcagaat 123480 ttgttaaaaa ataatttcaa tctcaaaatt tctcattttg attgctgttt tcctgatttt 123540 gttgaattgt ttatctgcat tttcttgaaa ttcattgagc ttccttaaac aattactttg 123600 aattctttgt caggcagttc atatatctcc atttctttat ggttggttca ggtgccttat 123660 tgtgttcctt tgactggtgt cacgtttccc tgactgttct tgatccctgt agtcatgtgt 123720 tggcacctgc acatttgaag aagctgagac ttgttccagt ctttgcagag tgactttatt 123780 gggtaaagcc cttcaccagt cagcctgtcc agagattatg cagcctgagt ctaccggggc 123840 tggcctggag tctgggtcag cagggtaggt cctggagcct tggtacacag gtgctgctgg 123900 cctggcatcc tggtctacta gagtgagcct gaaccttgga tctgcaagga ccagtgtgaa 123960 ggctgggtag gtggatgttg gcctagaatt tggatcacaa ggggctggcc aagtactggg 124020 tttggaccct tgttctgcag tgatgtgagg ccacaggggc cgatctagag ggcagggctg 124080 cagggaccac cctagcacta gacaggctta gagcctaggg ctgtgggatc cagcttggtg 124140 ctggggtggg cctccaagct tggtttgtgg gtattggcct gaagtttggg gccatggggg 124200 cctgcctagc attgagtttt actggggcga gctcaatgtt agggtctaag tctggtgtac 124260 acttcccctc cttcccccag gtgaacagtc tctctctcca tgctgggatc tcagggactg 124320 agggaggtgt gacacaagta atgtaaaact gtccttctta cccttttcaa tgtgtctttt 124380 cttatctgtg tgccacattc aggtaatctc tcgtctggtt tcttagctct tatatttttg 124440 tgtgtagaca gttgttcaaa ttgatggttc tacaatgaga tgagtgctgc aaagtgctag 124500 tctgccatct tgctgttatc tagacctcag gcttttctta aaacaactca acactttggt 124560 ctggcatccc aacctttcca atcatggcca tcatccacag catataaatt caaatactcc 124620 aatgttaaca tcttatgcac atgccactaa tgattctgtt ccatcagctc tgctaatatc 124680 caaccctaaa ataccatgca taatcttctg gctattggag aaaagtcttt aaatttcaaa 124740 tgtgataaag tctttaatct taactagtca ctcagtggaa tgagattctc ctactctgat 124800 acggtttctg atttcaggta gccagccagt caagactctc aacttctgat ccacttcttc 124860 acccattccc ctcagtagct tcctaagttt tcagtcttct caaaacctct aaacaaacct 124920 tgtattccac aaaatattat taaaaaatgt ttcataaaaa gtttcgtggt cactaaccta 124980 cagtaacata ctaccttata tccactacaa tgactactat tgaagtacac acacacacac 125040 actctcacac aatatgtgat ggcaaggatg tagagaaact ggaccccttg tgcactagtg 125100 gtagaaacgc aaataggtac agttgctctg gaagagtatg gcagtttctc aaaattttaa 125160 aaataaaatt accatatgat ccaacaattc cacttctggg aaaacaattc aaagcagggt 125220 ctcaaaaaga tatttgtaca ctcctgttca tagcaacatt atctgtaata gctacaacat 125280 ggaagcaacc tgagcgctca tcaacaggta aatggataag caaaatgtgg tatatacata 125340 caataaaaca ttattcagcc tgaaaaagga tgcaaatttt gaaacatgct aaagatggat 125400 gaaacttgat gacactgcga agtaaaataa gccaatcata aaagggcaaa aactgtatga 125460 ttgcacttat agggggtact tagagcagtc aaaattagac acaaagtaga ataatggttg 125520 tcagaggctg tgaagataag gaaatgagga attattgttt aatgggtaca gagtttcagt 125580 tctgcaaaac agagagttct gatcgtgact gtgcaacaat attaatatac ttaataccat 125640 tgagccaaat acttaaaaat ggtgaaatgg aaaattttac attatgtgta ttttactaca 125700 attttttaaa gcttaaaaga caagtcacat ggttgggtca cataaatttg agaaatacat 125760 tttatagtcg tttcttgcag attcacaata tataccggca tttaaataag gttccaatat 125820 tttcagtaaa aaaatcttga tttttccacc ctcacccaca attacaatta atatcacaca 125880 tccatcttta cttccttgtt ctaatttcat tagatgggca tctttcctct tattcaaggt 125940 caatcactat atctgcattt ttcttttttt atattacctg tatgagagat acacctgtat 126000 ttttcattcc aacccttaat acctcgaaaa actttgcttt gataattact acctctatta 126060 tctgaaacat ctttagtctt cacaataaat cactaaagtc ttacttactt catgtcctaa 126120 atatttgtct taaatccaga aaaatttatt ttgaattcct attataccac tgtcattgtc 126180 aaggctctca ctgactgaac taccttacca ccacacgttt ctcttcaatc ctttctctct 126240 tgcaaggtta ttaaaaatac acgtttgaca aacttactat ctacctactg agcaaattct 126300 ttgctgactc cctaatacct tctatcacat cttatcttct tcattttcct acctctcagc 126360 tagtttatga tctaaaagtc ctcaactgcc tattgtcccc tactccctat gctgcttcta 126420 actttggctc atacttctgc ctggaataag ccgctcatgc ttctagctgc ctgattccca 126480 gtcacatttc aagactgaac ttagcatttc ctggccactc ttacttccct gccatctaca 126540 ctagattcct attgcatacc tgggtactcc agtactcctt catgttacta ttgtattttg 126600 gataccattc tacctcagtg actgaaatta tttgcttctg catctttcac tcttgagtat 126660 aatataaatt tctgtagggt gaaaactaat tattacgcat ctctgtatct ataacatagt 126720 acttgatgcc ttaaatatgg taggcgttga gactgttaaa ctcaactctt tcctcaacct 126780 ccctatttcc ctacaactgc taccagggaa gcaaaaagac taagaattta ggcgtgtgca 126840 tttatctatc tagtagtaga aacctagtaa actgttaccg aggtttagag ttatctgata 126900 ggaaaaaaag taggtatgtt cctatctccc atttactgct aaatgattcc tttcttttaa 126960 ccagaaatta tttccaaata atgtgacgta atttaaagca gtctagggca actcaaaata 127020 agaaccacag tctcaaccaa gttacactta cattcggcta gcttcaatgt cgtcagactg 127080 aggttctcct gatctgtaaa atgcaattga gaaacagtta gcaaaatatt ccatattcca 127140 aaaaaaaagg tagacatatt acttaggaag acaattttgt aaacaagatt taagcactaa 127200 ataaaacagt tttaaaatta aagatgtcaa catgaaagaa agtggtcaga tcaggtggcc 127260 atacaacaca tttattttaa gggttggact attaaaaaac tcaatgcatg ttttttaaag 127320 gaaactgtaa acgctataca tagataccaa cagacaagcc attataagcc ataattattc 127380 acaaagtcaa atacgtgtaa taaaacacac aactaaaaaa cttcctatag ccaagtattg 127440 gttatccaca ttaacaaagg tactcactgg tattcactca cagtattaaa ctttagatta 127500 gtggctcagt aaactactcc ctaggcagac agactaaagc ttaggccagc catgtagttt 127560 tgtaaatgaa gttttattgg gatgcagcca tactcattca tttaggtatc atctatggct 127620 gctttcacac taaaagaaca gagctgagga cttgtggcag aaaccacatg gcccataaag 127680 cctaaaatat ttattttctg gccctttaag aacaaatgtg ccaaccgcta ccgctactcc 127740 agacaattca aactaaaatc taataccttg gtaagtttaa agacacttaa atcagataca 127800 acattctaat gatgattatc ttggttcaac aatgaaactg tttccctaaa aatacactta 127860 ctgtatgtat tacctgtcaa aagtgtatca cctgaggtga agttttgcac tggatagctg 127920 tgaattaact tcagttttaa acagttgcca gttactttgt tatttctaaa tatactactg 127980 ctctctcatg tagaaatatt taaaattcta agtcactaaa aagcctttca ttttcatttc 128040 acgagatatg aatcagtatt tccctatcta ttcactttta taaacagcat cagcaacaat 128100 gaatgagtca atataatatt gatttctaac acttagaaat tcccaaacta gataaaaaat 128160 gttttttgag gtcaaaagct aaattttcaa attggcatta caaagtcctg atttgtgaac 128220 ttctcactga ctttaggctt ccaactttaa gcaactctaa caagaatctt aaaatcagtc 128280 acacacacac acacacacac acacacgcac acacacaaac ctgttttcta aatttcttag 128340 ctaaaaacaa aaacaaaaac aaaaaacaac ccctcacttc tttatcagac tctcaaaatt 128400 accctcactg caattcattc agattccaag gacaagaatg gaaaaggaaa aaaaaaaaaa 128460 aaaaagactc cagcagctca aatatttatt ttagatcttc tttgcaatgt atttaaattt 128520 tcaattttgc acaaaattac ataacaacta aaaactgggg catgctggag gtggcagtga 128580 cttggctgtg acacaaatgc aaaaatttca ctccaccctc tcccccaggg agcaagcaaa 128640 tcacctatgt gacacacctg gtctccacca gccttgtggg taagtacccc aagattgctt 128700 ccaaacttgt atctcccaga cagaagagct aaaaattgat gataacccca tgtaccagct 128760 gactcatttt tgaaagtgcg accctccagc atcagatgtc atactgtaag gaggcagagc 128820 tggcttgcaa aacaaaaaat aaacctgctg gcactgaggg aagagaggca gattagaagt 128880 tttcaaacac gtaggcagca aaactttcaa aattaacagg gaaagagaag agagggaaaa 128940 aatgaggaca tgatgatagg aaaataaaaa tattactgca aaaaggtaag acacaagaag 129000 aaaaacaaat ctaagtctta gaagtacaat atgtaactgt tacaaagttt tgagatcctg 129060 aaatgggata gagtttaaat acattatcaa atgataacta catctatctt cccaatttct 129120 gttccctaag caagagaata tgtgaacttt ggcatcaaaa tgtttgccac caaactgtaa 129180 catattaatt actacttttt acatatatta aagtaggcta ttaaaaacca ttgataagac 129240 aagctaagta atttaaacca atccagtata gaagaagaag gattgaaaga ttattacctt 129300 aaaataaatc tgtcctgggt ctattaaaca tagcaaagtt gttctactca aattggaaat 129360 tgttttttaa tcaagagaaa aatgaatata tgcagaacta gcagacattt ttcttgcagt 129420 aatttataat agtttctgtc tgaatgaatt tctactcatc ctaataacag tatatttcta 129480 gaatattata aataagttac caaagtcccg aggttagaat tcaaactctc aaaactatga 129540 catatgccag gtgtggtagt tcatgtctgt aatctcagca ctttgggagg tcaagacata 129600 aggaccactt gagctcagga gttcaaggtc aacctgggca acatgatgaa acctcgtctc 129660 ttagccgggt gtggtggtgg gtgcctttag tcccagcaac ttgggaggct gaggtgggag 129720 ggtcacttga gcccagaagg tcaaagttgc agtgaactgt gatcgtgcca ctgcactcca 129780 gcctgggcga tggagtgaga ccttgtcttg gaaacaaaca taaactatga aatatatacc 129840 acctagcaac agttcccaag cttgactttg gctcctaaag agtctactta ttcttttact 129900 gccaagttgc tggaagtaag aatcctgtat gtgcttgtaa atgcagaaca tataacctaa 129960 ttcaaaacat ataaccaaag ggaaattttt gtattaaact attgacttag gttatcctaa 130020 agtgtgtcag aataacaagt cagaaatttt aaaactgaaa caataaccaa ataacattgg 130080 ataataaaat gtaaatctca gaatgagaat caattttagg tcttgatttg aatcgcagaa 130140 aatatgatca caaaacaccc actaatctga atactgcagc atgagctagc aaattcaaat 130200 ggtggctcac ttccaataac actggtgcag cttctccatc ctgcaagcca ctccttttac 130260 ctccactgta actctctagg agagaaaagt atactagttt tattaatgtt ataaaaactt 130320 ctagagaaat gtttagttaa aacgttcacc acataaaagg catactttaa aatgcatatt 130380 aagaaatttt taatgttttc tataatgttt atagtaaaat gtttaaaacc ttgaagtttt 130440 tttgagaaat actttcctgt ttatacatac agataggtct ttgatagtgg ctactgatat 130500 ttttaatgag aaaaaaagac actaaaatat tttaaggaga ttaaatgaag taggtcaact 130560 ctcaggccca ctattcttag cagtattcct gccaactata cattgtcttc atttttacag 130620 tatgtatttc actttacaat gacagccttt taaaggctgt aaaataattc aaaattacct 130680 tttacaagct gtggccattc ggtgacatca gggtgatcac agctttgagt cactgattaa 130740 aaacaggttg tcacaccagt ctagctgcta ccttgatctg agcgtaggct taataactct 130800 aataaattaa acaaaccttt ggttagaaca ctttaatata taaacccaat tcattgttca 130860 aaaaataata ttcaaagctt caaattaggt gtcaatgtaa aattcatcag aagagtaatt 130920 attatagaaa agtttttaag gactattttc cagcattttg tttttcttaa atgatctctt 130980 catttgagaa aatgtaataa ttccttgtac ttttatgtaa tgttatagtt tctgaagcat 131040 tttggtcaat agtaccttga gtcttataac aactttggct ttacctaatc aagacagata 131100 atatactaag aattaaaaaa aaaaaaaatt aagcagcctc cgagtgatta actgacttgc 131160 ccaagatttt ggaactagtg ttgaaggact gactaaaacc cagatatact gacttcctat 131220 caagggatgg atttttttgt ttgttttggc ttagttttgc tatactgggt ttcaagattt 131280 aagtatatgt aaatgagtaa agattcagaa cacagattga gatctttcaa atacggacaa 131340 attcagtcaa aagattccta agctgataga gcaatcagtc accaaggagg gcaactgctt 131400 aatggaatag ttatatacat acacataaac acacacacat aaacacaaag tctagtccca 131460 ctaattctgt atgtacgtaa agtcatttaa catcagtcac cgcatgttct cactcacagg 131520 tgggaactga acaatgagaa cacatggaca caggaagggg aacatcacac tctggggact 131580 gttgtggggt ggggggaagg ggagggatag cattaggaaa tatacctaat gctaaatgac 131640 gagttaatgg gtgcagcaca ccagcatggc acatgtatac atatgtaact aacctgcaca 131700 ttgtgcacat gtaccctaaa acttaaagta taataataat aaaaaacatc agtcaaaacc 131760 ccttaagtac tgcataaaaa tatattctac tctttcttgg ccataaatct actaagattt 131820 aatttcatga aaaagtatgg caaaagatga aagcatatcc tcctccctca accaaatatc 131880 tttttaaccc cttacatggc cttagctgaa cttttctgat tgtcacagtt caaatttagc 131940 aggcctcttt actgacactg tagttctggc aaagatacca tacatctgaa atatcccagt 132000 atcaaaagat cattttgtgc aactagttct ttcccctcac gattccccta tccaggccaa 132060 atctgaggca tcaactacgg aaagatgagg aaattaggag gaagaaacct ttcataatta 132120 acatcctcaa agcaacaata gtcaagcgta aaaggtggtt accagtgtgg attcagaacc 132180 caatataaaa cagcaaggta tctgcgaata ccaacggtta aaacatgaat gtttgagccc 132240 atacctatgc agctatgaac gcagggcttc aaaatccaga ttaggtgagg attggcctga 132300 atatataaaa ataattgcag gggattccaa taaatgggat ttatagtatc tgtaagaaat 132360 aacgcaatct cccagatact cctatcctaa ctatacattg cctaataaga acttagacat 132420 tgctgaggtc atatgggaaa caccaccttc cctaaaataa acaatgtggt catgatacag 132480 cttccccttg ggttctcaag agactaatgg tatgtggaat tagaagattc aaacaagtct 132540 aactttccat cttgtaaaca caaaaataat aaagttaaaa tatcttttaa ttgactaatt 132600 gacctcaatg taattaaaga gctatatgta ttttgaaaac tagagtcaag tcctctcttc 132660 cagtcccctc ttttatgaga tccggtgctc aaaaggctcc aaggccaggc tggacttatg 132720 tctctgtttg gtcattcact agctgagaaa tcttgggcaa gttacttaac ctctccgagt 132780 ctcagtttcc ttataggtag aactaggata atagtaccta ttccatagag ctgtcatgga 132840 taaacaagct aacatctaag tatctcagaa cagtgcctga cataatgtgc tcacaaatgg 132900 ctgggcgtgg tggctaacgc ctgtaatccc agcactttgg gaggccaagg cgggtggatc 132960 acttgaggcc aggagttcga gactagcctg gccaacacgg tgaaaccccg tctctactaa 133020 aaatacaaaa cttagccagg tgtggtggca cacgcctgta atcccagcta cctgggaggc 133080 caaggcatga gaatcacttg aacctgggag atggacgttg cagtgagtca agaaggtgcc 133140 actgcactcc agcctgggca acagagcaag actctgtctc aaaaacaaca gcagcagcag 133200 cagcagcaac aacaacaaca aatgaaagct attattaata ctcatagccc aaaatccaaa 133260 cctgccctct caatcttttt atgcatatta ttttacctct catagcacac taatctcttg 133320 taaatttttt cagcacccta cctgggtccc tcatacagtc ttggaagtgt agttagtgag 133380 cacctgacac aatgctttaa aaatggcagg ggcccaaatt tgctgaacac atctgtcatt 133440 attatgacat taagatacac atgcaatacg aattccaaaa aataaaacaa aaacatacca 133500 tatttcgcca aacttctgag gagctggtga attctaaaat caggctctta cagattttta 133560 acctaaaata taaaacacct cactcaattc tttttacata aacaactgga tgaactttca 133620 aaaaaaaagg tactaaattt catcataaag gcaaatttat tttctataat tatgaacatc 133680 caaaaacgta tcaagaaaca aattactgct gttgccggga tgaggaaagc ataggtaggc 133740 aggccctgtg gcctgagtgc tttcagcagg caaagccata tttcccatat tcatccataa 133800 agcttagtgc cttctattta tttactctat cctccctcca aaagggctaa acacatatga 133860 aaactatttg actatatccc tctaatcctt tcaaatacct atagcaattt tgtttttaat 133920 taaattctat atgctaagca tcggctatgt taggtacaaa tctgggcatc taccactttc 133980 tagagtagca gccttgggcc gaccctctga cccttgagtc tccaatgtca ggttattgta 134040 gcagagaaaa tgcgttaaaa agttatagta taatgcctac ctggcacaaa acaggacttc 134100 aatatacgac gataattata atttattaaa tcaaccactt aatatatatc aaaacttaac 134160 tcttaaaaaa aaatcctgaa gcttaaagca agcccctaaa ttatcactgt aaattcttaa 134220 cttgtttgta tacaatcaga acattcctca atggaacaaa aataaagtcc tttcatgtac 134280 tgcattacat ataaagaaag caaatctcaa aggttaagaa acctatccag tgtcctagag 134340 gttgatggta gaaagtgaat acactgcata taaaacattt tgaaataaaa ttaaccaact 134400 tttaaggttt tagagactga ctttcaaact tcagtctata atagaattac ctggggaaat 134460 ctaaaaatgc aactacttgg gctctactcg caaagatttt cattcagtgc atgaagtagg 134520 ggtaaatgaa tttttttttt aatttttttc agaccaaccc aagaacgcag aaatgaattt 134580 gcattttaac atatacttca catgacacac agatctcatt ttaagaagcc ctgccttcca 134640 aattatgagt taggaacaca taatcatgga ggaaatatac caaatctata aaaatacaga 134700 ataacaaaaa ctgtaagcac tacaaatatt aggcacactc acttgccaat ttaaccataa 134760 gaatcctaat accagacata gttctcttac tttatctctt caacagaggg ctcagtctaa 134820 taatcttata aataagtata gtctaataat aaatgcctat gttgatctat atctacctcc 134880 ctaaaatttt cattttattc atttctattt ttccttcacc tccttctaaa gctgtttcaa 134940 aacttaattt cacaaactgt ttttttctat cactttttat tataacaccc aacacttctg 135000 ttctcctttg catcatgttt atggtgtctt atatttatgg ataatgctac ttattaaaac 135060 tgtctaagtt ttgtccgttt acacatttca caattaaagg actactacaa caattttcct 135120 aagtcctcct gctttagttt ctccttattc cagtccattc tgcagttaag acttaaaaag 135180 ttttaaatac tgctttcaaa taatacttgc aacataattc cctcaactcc attagctcct 135240 cagagtacca tttctttatc ttctttcctt ttactgccaa aaagacgtga aaaccactag 135300 ctcagctgct atttttctat ctactgaaat ttttcttgta aagtttccat catttctgta 135360 tattcccagt gctttggccc cttaatccta cttaattttt gtagctttta agactgctaa 135420 tgactcctca cctcctctgg cttccctaat gttgtatcca ctcattttct tccatctctc 135480 taaaggcaat aaggtcttct gctagttcat cttcctacct catacatggc ctctctccaa 135540 gtttctgtca atagccactt ttcttaacct aaaccaattt tctgcgcaat gtcatccatt 135600 cccatagcac ctctatgctt acaaacccct aactctgtat ctttaagtcc ttatgtctgg 135660 catggtatgc ctgcaactac atattaccaa cggtacacat ccatttggat gtctcattaa 135720 catctacatt caacgtatct aatatcaaac tcaattattt tcccaaagaa ctcactctgc 135780 ctaatctcac tgtcctggtt aaggactaaa aaaattggtg ccattcatta ctttctcccc 135840 ctcattttta tttgccctaa ccactgtgta ggttgatact tgttcagcct tcaaattctt 135900 cataatcatt aattcaaaaa ctgtctacta gattttgagt gcctactagg tggatgaaga 135960 tgcagaggta gaaaaactag acataatttc ttgccctcat gtggtgaagg aaatgggcac 136020 aaataaaaac cacaattaat tatgcaataa caatgcacag ttaagtgttg tgatggagag 136080 atacaggggg tgttaagttg tgtactgtaa taaaaagtcc ttagtctgaa gaaaaggaaa 136140 accattcttt atgagggaca agcaagattt acaagacaca ctaagaaaaa ccctgtgagg 136200 taatgatggt agcactatca gtccagctgc tcaaattgga agattctcag tcatattcta 136260 aagagtctct ctctttccca gtatatcaaa ttgtttacca attgctacca attcatcctt 136320 agaaattccc ctacatttct acattctcac attattcccc agtctttttt gattgctttt 136380 agttgcttcc agaataaagc caaagctccc aatcacgtca gatgagattc tacacaattt 136440 ggtcaaaacc tgccagtgca gcctcttctt acagactaga ccagacttca agagaacatg 136500 tgtatcattt gcttttatac ttccagtgct tgcaaatgtt tatagaataa gcatcttaca 136560 aaagagaaaa tttttctctt agggaactag ctttcagtcc tttagtaaat gcaaggttaa 136620 gattcaaacc ctaatttgtc tgattctaaa gaccacgctt attcccttgt acttgccttc 136680 taatttatac tcaaacccta tgaatttcct taaaaatatc tcttactcct tttttcctca 136740 aacttaccaa cactgtccta ctacagtgcc ccattatttc atctggtttc ccttttgcct 136800 ttatcctcaa ctttgccact agaattatct tcctaaaaac tcaaagttac acatatcatt 136860 ctatattcaa aagctttaac actttctcat gccaacagaa taaatttcta actccttcac 136920 attttatttg aggcccctgc catgtggccc tgaccccagc catcccagca ctactgccca 136980 ctatatgaca tcatcaccag ttaccagatc tagtcccatc atttgactat tggctataat 137040 gtactggata tttgtgtttc tgacttcaat gcttttgctt ctgaggagac ttcactcgga 137100 aatggtcctc tatccattac taacctctat cccccaccca cctatcatgc catgttaaaa 137160 actggcctca ttctaaacac tgtatctcac agggttatct aaactcttat acataatcac 137220 catctccttc atgtcttatt atacattctt aataccataa aataatttat taatttctcc 137280 ttatatttat tatgttatac cttacattac agctatctgt atacatttgt cagtgcctct 137340 agttgtaagc tgattgatgg tagggatcat ctcttccata ttttactttt cgtaataatg 137400 gtgactatgt tttcttgaca ccatacctcc cctctacaag aaaaaaaaaa aaaaaaaaaa 137460 ggaatcagga cccatggcct ttgagctagt tccaaatgtg actcatagat gaacaaagat 137520 accatttctt cccaaattaa cacaaatata agtaaatgcc aatttaagaa acgttttttc 137580 aaagactaaa tatgtaagaa taaccaaaac aattgtttct aataatgttc ctttctctac 137640 cagatattaa aacatattaa cttaaatgga ataattaaaa tcggcatgcc tttaaaaaac 137700 tgagtataca ctaaatatat gcatacctta tgacttaaaa atttcactct taagtatacc 137760 aaacagaagt aaacatattc acaagaagac aatcactgaa atgtttagag cagcagcaat 137820 attcttaaca gttccaaacc aaaaatgatt aaatgtccgt aacagcagat taaactatgg 137880 catattctta aaatggaata tcacttccat tcttaaaatg gaatatacag cgactatcat 137940 aaacaattac tacaaccaac aatgtgaata aatctcacaa atacattaaa agaagtcaga 138000 cacaactaaa tgtgcttgat tctagttaaa ggatgaaaac aggcaaatct aatctatgct 138060 atgagaagtc aggacagtgg ttacacatgg aagaaaaggg gtagtgacac agagcacaag 138120 gggctacgca ggagctgctg ctgttttttg atctgaatgc tagctaaacg ggtgctcagt 138180 gtgtgaaagt gcaacaagct atacacttag aagtgtatag cttaaaacat tctaaaaaaa 138240 aaaaaaaaaa cctcatatgg tattagcatt agacaaagag gtaagcacaa caagcacaac 138300 agaaagctaa tttcagagaa agatccgaaa gtatctgaca gttgctcctt ctcaaacgag 138360 aattttcaga ccttggataa caggcagcag aggactataa tgcatgaaag gacaaaaaca 138420 aaggaggtga gccatccact gcttggatgt ctgcctggag gtaatttcca acctgcagtc 138480 aatggagggg aaatccagtg agaagacagc agttttactg agttcagaat caagagatca 138540 gagctgagaa agctgaagtg ggtaaaattg atgacaagtg ccagacaagt gcttgtctga 138600 gaaggcagag aaatggcttc agaaatctgc catttgagag tccactgctg agtactaact 138660 gtacacgatt aaggtaagtg actccatgaa gctagtgaaa gaggggcagt aagctgaaat 138720 attcccagta cttataaagg actgggagac tcctaaaatt ctctctaacc tgagtgaaga 138780 gaacacggtg acactgggag catttagtaa agactcagaa ggatcatgcc ttaggtagga 138840 gctactacca ttaaagcaaa gccttctcta gacaaactcc aatgtagccc tgaagggata 138900 aaactgacca gcaagttatt taggtggcta caaaacaaaa cactctaaaa gaaaacaaaa 138960 tctagacacc caacaacaaa atattacaat gtccagcatc caatcttaaa aaatcattaa 139020 atatgtaaaa aacaaaaaat aaaataaaat aaatactagg aaaatacaac ccatgaccaa 139080 gagaaaaaac caaccaacaa attcagagtg aaaaaattca agaaatcaat aagtaacctg 139140 attttcaaac agctattaca aatatgctca agaattcaaa aaaatacatg aataaaatga 139200 atcaaatgga atttcttgaa atataaagcg aaatatctga aattatttaa caagggagga 139260 gaaaaaacag taaaatagaa gacaaagcaa actgaagcac agggaaataa aaagactgaa 139320 aaataatgaa tatgatgtta atgacctgtg gataatacca aacagtctaa catatgtgta 139380 actggagtcc cagaaaaaga ggaaatgatg aaagaggagt aaaggtggta aaaaatatat 139440 atatagaaga aacaatggca acaatcttcc aaatttaagg aaaaccataa atgtacagat 139500 tcaaaaagaa aaaaaaaaca aaaccccaac aactctcagc atggtaatca ttgtgcaaat 139560 atcatagaac gtacttacac aaatctagat tagatggtat agcttactac agaactagga 139620 tacatggtat agcccgggtg ctcctaggtt ataaagctgt acagcatgtt actatactga 139680 atgaatactg taagcaactg taacaaagtg taagtattta tacatctaaa cctagaaaag 139740 gtacagtgaa aatatggtgg tataatctta aatgactatt gtcaactatg atctcgttga 139800 ctgaaatgtc agcatgcggc acatgactgt ataaccagac ttctcatcaa aaacaaatgc 139860 tgaaagaaaa acacatcaac taaccaagaa aaaagaaaca tatatgtcca cacagagact 139920 tcttttttta cacaaatgtt cattgtacct ttttataata gctgggaact gaaaacagcc 139980 tggaactgaa aacagcccag gtgtccctta acagatgaag tcacaaacca ccgaaacatt 140040 caacaatatg gatgaatctc aaaaacatta tgttgagcaa aaagaaactt tttacaacat 140100 ataagtattg tatgactcta cttacataaa gttctgcgca agctaaacta agatgaaaac 140160 aatctgaaca atgttaggtt ctaggggtgg tgtgggggga aggaataact aggaagaggt 140220 gtaggttcta taccctgata gaactttctg gcaaaggtgt atacatttgt cacagctcat 140280 gaaatggtat atgtggtcaa ctgtattttc caaagatggt cacaatagaa gccattccac 140340 atgctcttaa caatgtaaca ctgtcatttt ttcatcaggt ggtggagtct atggcccttc 140400 tccttgaatc tgagtgaaat tagtgagtct ttcaatccaa agactacagt catacctcaa 140460 ctatctacag aggactggtt ccaggactcc catggatccc aaaatccaag gatgcttcga 140520 atcccttata taaaatggca tggtatttgc atataaccta catgcatctt caaatatgtt 140580 aaaccatctc tagattactt ataataccaa atacaatgta atgctatgta aacagttgtt 140640 acaatgtatt gtcaaagaca agctctcctt gccaatccct gaccaaatga gagattcatg 140700 agcaaaataa atagttgctg atatttaagg cactaagttt ggggcaatgt attacacagc 140760 aataaataac tggaacagca tagtaaattc tagttaaaaa tactaaacta ctaagtttta 140820 gttaacatac atgctcaagt taagggtgtg gtatactaac aactgcaact tactttgaaa 140880 agcataaaaa aagacactag aagaagacag gatggataga tggacaagat agaagacaat 140940 aacaaataga acaaaatgtt gtgaaattat attctacaat tattttaaag tctgtgtggt 141000 ttgaaaaatt gtacgataaa atgaagagtg aaataaagac atttccatac aaa 141053 <210> 2 <211> 150237 <212> DNA <213> Macaca mulatta <220> <221> misc_feature <222> (64387)..(64600) <223> n is a, c, g, or t <220> <221> misc_feature <222> (76284)..(76747) <223> n is a, c, g, or t <220> <221> misc_feature <222> (134705)..(135171) <223> n is a, c, g, or t <220> <221> misc_feature <222> (145964)..(145983) <223> n is a, c, g, or t <400> 2 cagatgtgca gccctccaat aggacaaata agactctcag agcctggctc tatttgggga 60 tccctcagtg acaacagagt acccctgtga gcatgccttt tctatctctc ctgagagggc 120 agtagcatgc tgtcttagga gtcagtatgc tctttagtat gcttagtcac ccaagacttg 180 ctttaattgt agatagatac ttacatatag gaaagatgtt cttaagtaac aaatgaaaaa 240 ctttagaaga ttgaattaag ggtcaagcaa ctgtgatatg tctgcaaatc tcattagtgt 300 tatgctgaaa gaaggaaata tggcatgcct ttattaaata atgacaatgg aaccacgttt 360 cgtgctttgt tatttttact gtggagtatt ttctaagatt atgtttgctt ttttttctct 420 ttcatgtttt gctgagatag aaggcctgga gtctgatcct ccacttcaga gaataggggt 480 gagtagctaa accattatct tttgaaattc atatgtcatg tgctttttgc taggtcttta 540 ggttgttgtg tatatctttt cagaagctta ttgaaggaca ttttgatgat acgtcctttt 600 cctcattgag accctcacca tgtcacctac actattgaat ctatcatttc tgttttaatt 660 ttaactctct tctgctttta tggaaaaatg tagaatttaa gagaattttt ggcaatttca 720 tattggatca aaatttattg tagtgaaatc caggtgtacc aaaatattaa cagagtttcc 780 tcatctgttt aattattggg gtttcagaat agagactcca tggttcataa gatctttgtg 840 gtcatactac attatatttc tgcttctaat tgaattatta agtattgact tgaattagtc 900 tttttctcgt tgttgcagca aggtaagtta tataggaaat tttcttctct cgatggcatg 960 cctgagataa tcatagatat aagacacctg ggtggtttct agtatgcgtg taatttttgt 1020 ttcttgatct gtgtgttgag tacttgctgt gtttgcatca tgcaaataca ttgagcttta 1080 caattttagt ggatgcactt ttctacatgt atattattct tcgatagaaa gtaaaaaaaa 1140 acctcatcaa actagtcaaa atattggtta atacataaaa aagtctcaag tagattgtgt 1200 attacatggt gcttattgat cgatgccctc ataatagatc aagtacgttc tctctttagc 1260 ataggccttt ttagcaaatc gtgtcgtgag tagttactca agtattttta ttttaacaca 1320 tttatgtttt ttctatgcat attcttaaat tctcttacac ttttttctct gttataaaaa 1380 catgctgaac aatctcaagt cttaaagatt gcagtattgt ccctacatat tcatgtattt 1440 tggtactcaa ttctttatac tttctttgac agatcacttg aacatgtctc ttgttttgca 1500 gagagggaat tgatgggata ccttcatgct tttctattct atgtgctaca taattgaata 1560 tacaagcaaa tatagttatt aaggtttagt atgattattt ccacaacaca tgcaaagaag 1620 tttctcatac atcttaatag aggcccacat gcattgtacg gttgagaatt tggggaaatg 1680 ttgatgaagt tgggtaaagt ataaatccaa aagtcagaac ggtgaactcc ttgcttaagg 1740 atctcctttg agattactta gtcaatacac aactgataaa tttaagtgct tttcaccttt 1800 tgagctctcg acacactaaa gctaaaatgt gtttcaactt ttaatcctgc ttccctaatt 1860 ttcccttttt tagtttaaga tcaaagagct ccagccataa attactacca agagtaacca 1920 cttcatttta agaaagctta gcaatataga agaatataaa attatttatg acagatgtat 1980 tttaaccttt tccccatgct ttccagagga aatatgttta atcatctgcc ctatattagg 2040 gaaaaaattt ctatgctaat acaagtatct atcaatcatt aatctttcta tataagatat 2100 attgatcata accaattaat tttattgtaa atgagcttta gatttgacat tttggtagta 2160 atatatgttg tacaatctcc tgaggtccta taggtcttga gatctctatg tcaaaaacta 2220 tagatgtgtc agtgtttctg gtgaatgtga aggacgccac attttcctta gccatttctt 2280 ctgttcagaa taatggttat gaacattttg ctactgcaag atatccatat atttataatc 2340 agaatatgcc agtttttatg cactcatgcc tctgtttctg tagagcgttc ctagaatgag 2400 taatgcttga aaattaggtc catgtggttt ctttaatgag atatagtcaa atcatgaaat 2460 atttaggtta ccattatttc agtaatgtat tagaatgtca aggtaaagtt atctacattg 2520 tatatataca cacaacatag atataattta aacaacacat acatttatat ttatacagaa 2580 gatatatatt tatacaacat aaaatatatt ttattattta aacataaaat atattttatt 2640 taatgtagat tctttttttt ttagtttaag actttgaagg ttaaaaaaaa atttttttat 2700 tattatactt taagttctag ggtacatgtg cacaacatgc aggtttgtta catatgtata 2760 catgtgccat gttggtgtgc tgcacccatc aactcgtcag cacccatcaa ctcatcattt 2820 acatcaggta taactcccaa tgccatccct cccctctccc ctccccacaa taggccctgg 2880 tgtgtaatgt tccccttccc gtgtccaagt gatctcattg ttcagtttaa aattcttttc 2940 tttaagaatg ttgaatattg gcccccactc tcttctggct tgtagagttt ctgccgagag 3000 atctgctgtt agtctgatgg gcttcccttt gtgggtaacc caacctttct ctctggctgc 3060 ccttaacatt ttttccttca tttcaacttt ggtgaatctg agaattatgt gtcttggagt 3120 tgctcttctt caggagtatc tttgtggcat tctctgcatt tcctgaattt gaatgttggc 3180 ctgccttgct aggttggggg agttctcctg gataatatcc tgcagagtgt tttccaactt 3240 ggttccgttc tccccatcac tttcaggcac accaatcaga tgtagatttg gtgttttcac 3300 ataatcccat atttcttgga ggctttgttc atttcttttt cctctttttt ctctgcactt 3360 ctcttctcgc ttcatttcat tcatttgatc ttcagtcatt gatactcttt cttccagttg 3420 atcaagtcgg ttactgaagc ttgtgcattt gtcacgtaat tctcgtgtca tggttttcat 3480 ctctatcagt tcgtttgtgg ccttctctgc attgattatt ctagttttcc attcttctat 3540 tcttttttca agattttttg tttctttgcg ctgggtacgt agttcctcct ttagctctga 3600 gaagtttgat caaccaaagc cttcttctct caactcgtca ttctccgtcc agctttgatc 3660 cattgctggt gatgagctgc gttcctttgg agggggagat gtgctctgat tttttgaatt 3720 tctagctttt ctgccctgct tttcccccat ctttgtggtt ttatctgcct ttggtctttg 3780 ataatggtga cgtactgatg gggttctggt gtgggtgtcc tttctgtttg ttagttttcc 3840 ttctaacagt caggaccctc agctgtaggt ctgttggagt ttgcttgagg tccactccag 3900 accctgtttg cctggttatc agcagcagag gctgcagaag atagaatatt gctgaacagc 3960 aagtgttgct gtctgactct tgctctggaa acttcgtctc agaggtgtgc ccagccgtgt 4020 gaggtgtgag gtgtaggtct gcacctagtg ggggatgtct cccagttagg ttactcaggg 4080 gtcagggacc cacttgagca tgcagtcagt ctgttctcag atctgaacct ctgtgctggg 4140 agacccacta ctctcttcaa agctgtcaga cagggtcatt tacatctgca gaggtttctg 4200 ctgctttttg tttagctatg ctctgtcccc agaggtagaa tctatagagg caggcaggcc 4260 tccttgagct gtggtgggct ccacccagtt cgagcttccc agcagctttg tttacctact 4320 taagtctcag caatggtttg cgcccctccc ccagcctcgc tgccaccttg cagttagatc 4380 tcagactgct gtgcttgcaa tgagggaggc tctgtgggtg tgggaccctc cgggctaggt 4440 gtgggatata atctcctggt gtgccgtttg ctaagaccct tggtaaagct cagtattagg 4500 gtgggagtta cctgattttc caggtgttgt gtgtctcagt ttcccttggc taggaaaagg 4560 gattcccttc ccccttgcgc ttcccaggtg agctgttgcc tcaccctgct tcagctcttg 4620 ctggttgacc agcaccaatt gtccggcact ccccagtgag atgaacccag tacctcagtt 4680 gaacatgcag aaatcacccg tcttctgtgt cgctcgcact gggagctgga ggctggagct 4740 gttcctgttc ggccatcttg ctcaggatcc aggttttttc atgtagattc ttaactgata 4800 aatatgttta acattattaa aatagattaa aataggttat agttaataca atgaaaattg 4860 gcagtcctat tgcaaaacgt atgccataac tacagcattt atcactgaca gtcataccag 4920 gatagtcttt tatttccaat cacttaaaca ttcctaattg caaaaaaaat ttgaagacta 4980 aaattcagaa gttttgaaag agccattgcc tggataaatt atacaggttt cagttttatt 5040 tataataatt atgtatatat ttataaatta atacataata aattaataac ctgtgatagg 5100 caatgcaaag atgacagtga gagggcaaaa ttgataagat tgataaagtt atgttaacat 5160 gaagaaatta accaggatac catccacact ataaagttag agaaatttat caggacagtt 5220 ctcaaatact cttctcaatt ttaacaatgt aacaggaatt tttaagattt tggtattatg 5280 tgtgtttcct tccagataat ttgaacagat tcatatttgg tattttttaa agccatatct 5340 ttgtccttag tgctggcaat gtattcttga gaatgaacaa atcagaaata tgtaaaagcc 5400 ataagtgagg gtgtcaggtt gaagtagtca atcaattata cagaacacaa agaattttat 5460 cttgtacgat gttcacataa ctttacagaa gtgtgctgaa agggctataa aacatggaca 5520 tgattatctc attgaaaggt ccaagaggta ctgaaataca tgcttttatt ttgaaccaac 5580 caccctataa acgttgtatg gcttatttag atgagcgccc gtgtgtgtgt gtgtgtgtgt 5640 gtgtgtgtgt gtgtgtgtgt gaatttgaca gggaagcaag agcatcaagt ttccaatgca 5700 ctctgactgt ggttagaatc atgctgaaaa catggctccc ccagttctgg aatgagccca 5760 cagatcaagc attcccagaa gacatagcag gctcaaatcc ctgtgtacac aatatttcat 5820 gattatctta tgtcagtagt ttcaaagtat acagtttgtg tgaagacaaa tccaatgtca 5880 tttttttttt ttttttgcta gcctatatgt gtggtaaatc cattatttat ttacttcctg 5940 aaaattacaa tcagattaag aaactgcagc aaagttggca tgatgagata gagactgaag 6000 tgtaagctta tgttaatgat gcccttggtt tggataaaca catctaagag aaaactgaaa 6060 aaacacacat ggcagggaaa ccttgataga gtctaaatat aggattgtat gtagtaatgc 6120 aatcaacaga tgagcatttg gcagtaatat tatttttcaa atatggataa acactgctta 6180 ggagagtaaa gagagacaaa gttgaaagca ggtttatagt aggtgttgtt ttagtgttga 6240 tccctttttg ctccaataat caaagtgata aatattgaaa atcgattcat gcagcattac 6300 ttgttccatt ctaattttta tatatgtcaa cagtgccatc tcccaacctg tgctgtcccc 6360 ttcaggagaa gtgactgtgc tgaagtttat aaggttgaca tattgccagc ttcaatagta 6420 aagctgaagt gtatactgaa ttcttaatgc aaataacaac tctattggaa agtaacccag 6480 ttatagaagt gctaatttgt caggagctgc cttaccaaga tcaatgatga cgatagttat 6540 ctcaggattc tgaaagattg ttttcagatt tcaactagtc tagctgaatg ttccttaata 6600 gaaagagagg acttttagaa ttggttcaat atgatgacct cctgaattat ctcacatagc 6660 ccctgtgtac atgcctttct tttctctcag aaaatggcac tatcataata gctttcttac 6720 gcagacttca ccttagggtt ttacagtaag ggaggggtct ggtgtttcat ttattttgaa 6780 ctatttgttg ttgattgtgt acagtgcttg agtaaaaaat ggaatatagg aacatctaga 6840 ataaattttt taaatgatca ggtgactaca aagtgaatta ttagtgtcaa aatgttggga 6900 aagttttaag agaatatagg aaacttggac attacacaat tacactggga ccaaattgtg 6960 gggtctcatt atagttagta tttatgtatt tttttccaat tgatttgtgt gccttttttc 7020 tgcatgtttt tggcagatag aatggctata acaagtaaga gtatgtcagg aaataaaaat 7080 aagcagaacc ctattccttt aaaattcttc atttgatggg agggtcataa aataagtctt 7140 aacacattta aagaattaaa ttcatgtaaa ccatgttaat ttaattccac aatggtatcg 7200 aattagagta agaggaatat ctcttactct cctaaatctc ctaatgtttg gaaatttaaa 7260 ttagcatttc tggcctattt attggtttaa aaaaagacaa aaaaaaagga aaattgaagt 7320 attttgaact gaataaaaat aaaaatatag aatctaaaac tgtatgggat actgataaaa 7380 caggatatag ggagaaattt atagcactga aatgcctata ttagaaaaga aaacaggttt 7440 taaatcagta aatttgtagt ttaccttaag aaacttagaa aagaacaaat taacccagag 7500 ttaagtaaaa taaaagcatt aataaaggta agagcagaaa tcaatgaaat ataaaacaac 7560 aaaacacaga gaaaatttga gaaaattaaa aaatagccca gtgagaagat attgataaaa 7620 cttgtaacca gaccaattta agaaaaaaag tcaaaacaca aataccaata tttgaaaatg 7680 taagagggta aatcattaca gattctatga atactaaaat gacaataagg aaaaattatt 7740 taaaaggggc atgtaagcca ggcatggtgg cttacccctg taatcccagc actttggcag 7800 gctgaggtgg gaggattgct agagctcagg catttgagac cagtctgggc aacatgttga 7860 aaccttgtct acacaaaaag tacaaaaatt agctgggtgt ggtgttgcat gcctgtaatc 7920 ccagtcactt gggaggctga gatgagagga tcacttgagc ccagaatgtt gaggctgcag 7980 tgagccatat ttgcaccact gccctccagc ctgggtgaca aagcaagacc ctacgtcaag 8040 aaaaaaaaat gtatgccaac atttttcaat aacttaaatg aaatggagaa attccttgaa 8100 agacacaaac tacaaaaact cagtgaagaa gtaaataacc tgaatagccc tgtatcaagt 8160 aaattgaatt tgtaattaaa agtcttccaa cagagaaaac ttcaggcaca tctagcttca 8220 tatgaaatga aaaaaaaaaa aaatgctaat cctctacaac attccagaac atttagaaga 8280 agggaatatt tcccaactta ttctatttgg acagcaatac ccaggtaaga aaaaaaggca 8340 cagaaattta aaaagaagaa tatacattat tcctcatgaa cataaatgca aagaaatcta 8400 atcaaaattt tagcagatga aatgtagaaa tactttatga ccaagtgagg gttacccaag 8460 gaatttaagg ttggttttat atgtaaagat caaccagtgt aggaagatca cttctggaaa 8520 gtcagagtaa gagcctccaa aaatctactc ctccataaaa ccaataagag ccttgacgga 8580 aatagtcgaa attaattttc taaaactttg gaaattaacc aaaggcttac aaaattccaa 8640 agaacattta tgcaagaaaa atggctgaat cagtaagaac agccagcttt gtggcatttt 8700 aatatgcctc cttcccatgc ttttctccct agtactgtag tagtcttaaa aattagcagc 8760 atagcaacca ctggagaaga agaaaggttt ggaaatttcc taaaaagttc cgtccccata 8820 taattatcac tatttgacct ctaaagccca atctatatga tttatattca tttggactga 8880 ctcagtgctc actaagtaag gaaatctcaa tttcaaggta ttggtcaaaa agaatccatg 8940 gcaattgttg actatcacaa ctgcctgcag tgttggtaac tgaattggga taaacaagaa 9000 gctgatcaaa aactgaaaac taaaatcttg ggaatgagat gtctagaggc tgtttcaaaa 9060 agctctgaca cattcctttt tatctagaaa gccacatgca ggctgggcgt ggtggctcac 9120 acctgtagtc ccagcacttt gggaggctga ggcatgcgga tcatgaggtt aggagtttga 9180 ggccagcctg accaatgtgg tgaaacccca tctctactaa aaatacaaaa agtagccagg 9240 tgtggtggcg cgcatctgta accccagcta ctcaggaggc tgaggcagga gaatcgcttg 9300 aacccgggag gcggaggtta cagtgagcca agatcacgcc actgccctcc agcctgggcg 9360 acagagcaag gctctgtctc aaaaaaaaaa aaaaaaagaa aagaaaaaag aataaaaaaa 9420 gaaagccaca tgcatgtaat tgtttacctc tggctttcct tttatgctct gggcaagtta 9480 aggaagagtt gtgaactacc taagtgctga atgggaacca taacacacac acacacacac 9540 acacacacac acacacacac acagcacctt aggaaagggt gagaagcatg ttagttagaa 9600 gcattaaagg aaatctcttt ctagtcatta tctgtgcact ataactgagc agagacttca 9660 gtatccacat actacagggc atataaactt tacagaatta gtccgggaaa atcatgtgaa 9720 aaaaaaaaca gcaacaaaaa aaactctggg aaaggggaga atatgatttg aagagtcgcc 9780 acattataca taatatgtct attgttcaac aaaaaagtac gagacatgca aagaaacaga 9840 aaaatatggc acaaatagga taagatgaag tcaatgaaat tatccttaag gaagaccaga 9900 tgttgatctt agtagacaga cattgaacca gctattaaaa atacgtacat agaactaaag 9960 aaaaacatgt cgaaagggtt aaagaaaggt ataaaaatac tgtcttacca aatatagact 10020 accaataaag agagagaaat tatgagaaaa gacaacatga aaaaatgtaa agcaaaaaaa 10080 ttagacagtt gaaacaagag ggcctctatt tgcagatttg agcaggcaga agaaagaatc 10140 agtgaacttg aagatacgtc aattgagatt atccagtctg agcaacagag gtgggaaaaa 10200 atgaagaaaa ctgagtaaca aagaaccgta gaacagcgtc tctcatgcca gtggatgcat 10260 aaactggagc cctagaagga tgaaaaaagg agaaggaaag ataacttccc aaattttatg 10320 aaaaacatga atttatatac ccgagatgac caataaaatc caagtaagat actctcaaag 10380 agatcatcac ctagccacat cacagtcaac atgtcaaaag acaaacaagg agagaattct 10440 tgaagatagt aagaaaaaaa ttattcataa catacacacc atcctcaata agtctgacaa 10500 ttgacttctt accataaacc atgcaggctg aaaaggcaat gtacataacc caagtgatga 10560 aataaaaact ttcaaccaat aattctagat tcaacaaaac tattgttcaa aaagaagaaa 10620 tgaagacatt cctaaacaaa atctcagaga aatgttctct ataagacttg tcctaataga 10680 aatgctaaag gaactccttc actctgaaat agaaaggcac tggagagtaa atcaaatcca 10740 cgagaagaaa taaagagaac cagtaaaact acatgtgtaa gtttaaaaca aagtataaat 10800 ttattttgtt tataacattt gtctttttcc tatttgactg aaaacataat ctcaattata 10860 aatttgtgtt gatggcatta tataaagatg taattttggg taatagcacc aaaatgtcag 10920 aataggagtt ttctgtaatt gttttcccac ataagtatca attttgacaa ccattcatga 10980 gcaagagtac cttgtgggag ttcaggagtt gacagtaaaa gttcagcaca ccagtggagt 11040 aaaaaaatct aagaatagat tcattggaaa gggtataaac agtttcactt tacctgcatc 11100 accctcccca aaaagtggca cagctcagta acaagagcct gttatttctt ccacagggga 11160 aaacaagagt ataataaatg agtatccagt ttctcaagac atacaggccc ctgcccaaga 11220 gatccacttt attttcatct cacccagaat actgaggtga tcagcaaggt ggagtggttg 11280 ggagagggta aagcaggaaa gagagatgag gactcacagc aacccacact tgaaactgcc 11340 atagatccta ccagttgctt catggactcc atcaggagcc cacctgtaag ccacttggga 11400 tgcaaaactc ccatcttgtc aacaaaaccc cagatgctcc aaatgcctcc cccactcttt 11460 ggctccccaa gcacactcct gtgaaaagca gcgagaatct gcagatggct tgcaagcact 11520 gttgacagct ggctgcactc tgcagaactg gaagaaagct cacaaacacg acaatttcag 11580 gacaccaccc taaaaaaatg agacttcagc acctggcctg cctttatgca acctggagaa 11640 ggtgatatgg tttggctgtg tgtccccacc caaatctcat gtcaaattgt aattcccact 11700 tgtcagagga ggggcctggt gggaggtgat tgaatcatgg gggtggactt ccctcttgct 11760 gttcttgtga taaagttctc atgagatcca gttgtttgaa agtgtgtagc atatccccct 11820 tcattctctt tcactccacc ttggtaagac atgcttgcta ctcctttgcc ttctgccatg 11880 attttaagtt tcctgaggcc tcccaaccat gcttcctgtg cagcctgcag aactgaactg 11940 tgagccaatt aaacttcttt tcttcataaa ttatccagtc ttaggtagtt ctttatagca 12000 gtgtgagaat ggactaatgc agaaggcata caaccttaag aatctgcccc cttgagggaa 12060 caagatgtgt ggagcaggtt catccataga caatgtctga gagaacctca aaatccctag 12120 cctgactaac tgatgaaaat gtttctctcc taaggccagt cagtaaagac cagagggggt 12180 gactctttct ttaaatgcaa aggcagcagt acagtaattc aagaaacatg aaaaatttta 12240 aaaaatgaca ccaccagaag aacacaatca ttttccaata accaactccc caaaaatgga 12300 gatgttcaaa ttggtttata acaaattcaa aacaattata ttaaggaagc tcagcaaact 12360 aaaaggaaca ccaatagact actctgtgaa atcaggaaaa caattcatga acaaaactag 12420 aaattcaaaa aagagaaaaa ttatcttaaa agaaaaccca gaaattatgg agctaaagaa 12480 tacaatgcat gaaatgaagg agcgtataca acagcaacgt tgatcaagca gaagaaaaaa 12540 atctgtgaac ctgaagactg gctatttgaa agtattcatc agaggattaa aaaaaaaaga 12600 atgaaaagaa ataaagccta caggatgtat aaaacatcat caagagaact aatatagaga 12660 ttattggagt cataaaggag aagagagaaa agggcagaaa acttatttaa gaaataatgg 12720 ctgaaaactc tccaaatcta ggaaaagata tgagcattca ggtatatgaa gctcaaatat 12780 ccccatacag gatacattcc aaaaagactt caccaaaaca cattataatc aaactgtcaa 12840 aagcaaaatc aagacaacga ataaaccaat gcaaccacca atcactaaga gggagacagg 12900 attcttatgt tgtgattatt atttacatat aatttcagta agtgttatta gaaaatttat 12960 aatgttttta aaaaagaaat ttgaaagcac tgaaagaaaa gagactcatc acatacaggg 13020 aaccctttta agtctatcaa cagatttctc agtagaaacc ttacaaaata ggagacagtg 13080 ggatgaacta ttcaattgct acaaggaaaa aaatgccaac caatgcttta cctagcaaat 13140 ctgttcctca gaaatgaagg agagataaga actttcctag acaaacaaga ggcagttgtt 13200 agatgaaaaa gaggcagttc atcaccacta gacctgcctt acaagacata ctaaggagag 13260 ttcttcaagc tgaaatgata tggcactagt tagtaatatg aaatgataaa cctcactggt 13320 aaaggaaagt acaaagtcaa atttagaaca ctttgatact ataatgatgg tgtataaata 13380 attttactat actatgaagg ttaaaagaca aaagtattaa aaaaaaaaaa acatagctac 13440 aatagcttgt caatgcatac tacagtataa aaagatgtaa attagaacat taaaaacata 13500 gcatgcaagg gtagggaagt aaaagtgtag ttttcatatg taatcaaatt taatttgtta 13560 tcagcttaaa ataaattgtt atacctataa gatgttttat gtaagtgtca tggtaactat 13620 aaagcaaaaa cctctagtag atatacaaaa gaaaaagaga aaggaatcaa aacactacag 13680 aaaatcatca aattacaaag gaagacagta agggaggaac aaagtaagta aaaagagcaa 13740 gaaaaaattt aacatgatga aaatagtaag tccttacctg tccataatca ctttaaatgt 13800 aaacggattg aattttccaa acaaaaacag aatggacaaa tggattttag aaacaacaac 13860 aacaataaac accacacaca cacacacaca cacacacaca cacacacaca cacacacaca 13920 cacacacaca cacacaccca gacccaacta tgtgctgcct acaagagatt tacttcacat 13980 taaggacaca tacaggctga aatgaaaaaa atagaaaaag atactgcatg cagatagaaa 14040 ccaaaagaga gcagaggcat ctatacatat agcatacaga aaagatttta agttaaaaac 14100 tatatcaaaa ggctaaggtc aaaatcgtga agcagttaat tgttccagaa gacataacaa 14160 ttgtaaatgt ttattcaccc aacgttgaag cacctaaata tataaggcaa atattaatac 14220 atataaaagg agaaatatac agcaatacat taatagtagt gaacttcagt atctcccttt 14280 caaaaatgaa tagataatcc agacataaaa tcaataagga aacatttaac ttaaacttca 14340 ctttagacca aatggatcta acagacatat agtgaacgtt tcatccaaca gtggcagaat 14400 tcacattctt ctcaagcaca catagaacat tctccaggat agattatatg ttagatcaca 14460 aaataatatt acaaaattta ataaagctga aatactatca attatttttc accacaatag 14520 cataacacta gaaatcaata ataagaagaa aactggaaat ttacaaatat atagaattaa 14580 catattcctg aacgaccaat gggtcaaaga aaaaaatcaa aataattttg tgacagcaaa 14640 gtagaaacac aacataccaa aacatacagg acacagcaaa agcagttcta tgaggtaagc 14700 ttatattaat aaacacattt ttaaaaagat tttaaataaa caacattaca cctcaaggaa 14760 ctacaaggaa ggaaaaaaaa aacaagcccc atgttatcaa agggaaggaa ataacaaaac 14820 tcagacagaa agaaatgaaa catagactag aaaaacaata gagaatatta acaaaactta 14880 tagtttttta aaaaaattaa atcaacaaac ttttagctag actaaaaaag agaagactca 14940 aaaaatgaaa gaggagacat tacaactgat accacaggca atacaaatta agagaaaact 15000 atatgccaac aaattagtta acttgcagtg ggtaaatccc tagaaacata caacctacaa 15060 aaactgaatc atgaagaagt ggaatatctg aacagatcaa taatgagtaa gggaattgaa 15120 tcaatattca aaaatctcac aaaaagaaaa gctcaggatc agatgacttc actggtgaag 15180 actaccaacc atttaaaaaa gaattaatac cactctttct taaactcttc caaaaacatt 15240 gaagaggaga aaacactttc aaattcatta taagaggcca gttttacctt gatatcaagg 15300 atttaaagag aacactttga gaaatgaaaa ttacaggcca aaaaccctga taaatataga 15360 tgcaaaaatg ttcagcaaaa tactagcaaa cctaattcag caacacatta taatggcata 15420 catcatgatc aagtgagatt catgcctggg atgcaggatg gttcaatata atcaaatcaa 15480 caaatgttac actgttttaa caggatgaag gataaaaatc atatgatcat ctcaatagat 15540 ttagaaaagc atttgacaat attcaacatc ctttcaggac taaaaaccct caataaatca 15600 ggtatagaaa gaatgtgcct caacacagta aaagccacat atgacaaacc tggaggtaat 15660 atactcagtg gtgaaaagta aaaagctttg accctaagat cagaacaaaa acaaggatgc 15720 ccaatctcac cacttatatg taacatagta gttgaaattc tagccacacc aattagggaa 15780 gaaaaaaggc acccaagttg gaaagaacga agttaaattg tctctgtaga tgacaagatc 15840 ttatatgaga aaacactaaa gactccacca aaacgctgtt ttagttagag cttaaaaaaa 15900 gaattcacta aagttgcagg atacaaaatc aatgtacaat atcaagttgc atttctaaac 15960 accaaaaaca agttatccaa aaaattaaga aaacaatcct atttgtgata tcatagaaaa 16020 tactaaagaa taccaaagaa actgaaaata aatggaaata aatggaaaga taacctatgt 16080 tcatcagatg aattaatact gttaaaatgt tcatgctacc caaagcaact tacagattaa 16140 gtgcaattcc tactaaaatt ccaatgacat ttttcacaga aatagaaaac acagtcctaa 16200 agtttgcatg gaactgcaaa agactcaatg aagcaatttt gagcaagaat agcaaagctg 16260 gagacatcac accacctaac ttcaaagttt attaatcaaa acagcatggc ataaaaacag 16320 acagaaagac caatggaaca gaatagagag cccagaaata aactcacatt tatagagtca 16380 actaacattc aacaaagcag ccaagagtac acaatgggga aagtatagtc tctacaataa 16440 atggcactgg gaagactgaa tatccaaatg caaaagaatg aaattacacc cttatcttac 16500 accatacaca caaatcaaat caaaattgat aaagacttaa atataatacc tgaaaccata 16560 aaatctttag gggaaaactc attgacattg gtcttggcaa tgattttttt gatatgacac 16620 cagaagcaca ggcaataagt gggaccctga caaactaaaa tgtttctgca cagcaaagga 16680 aacaatcaat catcagaact aaaaggcagt ttatgaaatg ggagaaaatg tttgcaaacc 16740 acatatctga taaagggtta atatccaaaa atatataagg aatgtataaa attcaacaga 16800 aacaaacaaa taatccaatt ttaaaatagg tgaagaacct gaatagacat ttttttcaaa 16860 gaagacttac aaataggcaa caggcatatg aaaaaatgct tgacatcact aatcatcagg 16920 gaaatgcaaa tgaaagctcc agtgaaatac cacctgtaac tattaggatg gctattatca 16980 aaaactcaaa agaaaacaag ctgggggaat gtagagaaaa gggaaaagaa ggcccttata 17040 cactgttggt gtgaatttaa actggaatag ccattatgga aaacagcatg gaggttcctc 17100 aaaaaattaa aaatagaact actatatgat ccagcaattt cactattgag catatatcca 17160 aatgaattca aatgactgtc ttgaagaggt atttgcacac tcatatttat ttcagcatta 17220 ttcccaatag ccccgatatg gaatcaacct aagtgttcat cagtagataa ttagataaag 17280 acaacctggt atatagacac agtggaatct atttagcatt cacaaagaag gaaatccaac 17340 ctttaaaatc ctttaaaagt taaactcata aaaacagaga ggagaatggt ggtttccaga 17400 aactggaggg tcagggaatg gggagatgtt ggtcaaaagg tacaaacttt cagttataaa 17460 atgaataagt tctagagatc tagtgtacaa cagcattact ataattaata ataatatttt 17520 gtatacttga aatttgttaa aagagtaaat atcaatattc tcaaatacac acacaaaaat 17580 agaactatct gaaggaactg atatgttaat tatcttgatt atagaaatca tttcatgatg 17640 tataatgaat atcaaaacat aatagtgtac atcttaagta tatacaattt tgatttgtta 17700 atcatacttc aatgaagcta gaaaaaaata tgtaattttt aagacagtaa taatataaat 17760 taagggtgag ggaactgact tatgttggag caaagttttt gtaaactaat cagtatccat 17820 tcaagctaga ttattttaaa ttgttaattt aattgtaata ctaaggcaac cactaaaaag 17880 ggctttaaaa aatacagtac ttgaggctgg gcacagtggc ttatgcctgt aatctcagca 17940 ctttaggaga cctaggtggg tggatcacaa ggtcaggagt ttgagaccag cctgatcaac 18000 acggtgaaac cctgtctcta ctaagaatac aaaaattagc cgggagtggt ggcgggcacc 18060 tgtaatccca gctactcagg aggctgacgc aggagaatca cttgaactcg ggaggtggag 18120 gttgtagtga gccgagatca caccactgca ctccagcctg ggtgacagag cgagactcca 18180 tctcaaaaaa aaaaaaaaaa aaaaagctaa tttcattagc tatatgaaat tctgagagac 18240 gaaactgaag tctccaacta taattgtgga tttgtctatt tctcctatca gttctatcag 18300 tttttgcatc acatatttga ggctctgttg tttggtgcat acacaactgg aataatcgtg 18360 ccttcctggt ggcttgatta ttttatgatt atatagagcc tatctttgtg gtatttttat 18420 ttactcttaa atctactttg tgttatatta atatacccat tcttttttta aaaaaattgt 18480 ttgcaagata catcttttcc attcttttaa tctcaaccta cctgtgccat tgaattcgaa 18540 gtgagttttc acatagagaa catactattg aatcatcgtt ttaaaaattt catttgccaa 18600 tcttctatat attgaggtaa aattcacata aaatttatca ttttaaggtg tacaatacag 18660 tgacatttag taatacacgt tatgcaatat taactctacc tgattactaa gtgttttcat 18720 catccaaaga aggaaacttt atactcatta agcagttaat tcccattcct tctccctgcc 18780 acgggcaacc acaaacctac ttttctatct ctatgaattt acgtattacg gatattttgt 18840 ataaattgaa ttatacaata agtgaccttt atgtttggct ttgttcactt agcatactgt 18900 gttttgatat tcaactatgt tgtagtatgt ctccgtttta tctgaataac tcagttcttt 18960 ttgttgtata cctaaaagtt gattcgtagg ttgtaataat aattctatgt ttagtttatt 19020 gaatagctgc caaagttttt ccatagtggc tctgtcattt taaaatccca ccagcaatgg 19080 atgagagttc cagtatctcc acatccttac caatatttat tattttatat ttttacgatt 19140 atagtctttc tagtggatat gcaatggtat ctcattgtgt ttttggtttg cctttcccta 19200 atgactaaca atgttgagca tcttataata tacttgttag ctatttgtgt ttagagaaat 19260 ttctattcaa gtgccttgcc cattttaaaa actgagttat cttgtcgact tatgagttct 19320 ttaatacagt aaactcttat cagatatgac ttataagtat tttatcccat tctgtaggtt 19380 accttttcac ttttgtgata gtccattatg cacaaaggtt ttgatttttg ataaatccaa 19440 tttatctgct tttgttgttg tttttgttgg tggtgctttt gcaaaaccca gtgtcatgag 19500 gtttttctcg ttatctttgg agaattttat agtttgggtt tatacatgta gattattgat 19560 ctaatttcca ttcatttgtg tgtatgctct gaggtagggg tccaaattca atttttgcat 19620 tgaattgaaa attcatattt caatttcata tttcaactgc atattcagtt gctgcagcac 19680 gatttgttga agagatcatt cctttccacg gggaatgatc tgcgactctt atcagaaatc 19740 aattgatcat agatgtatgg gattatttcg gactttagat cttgttccat gaatatgcct 19800 atttttatgc cagcaccgca atattttcat tactatagct ttatcataca ttttgaaatc 19860 aggaagtatg tatcctccaa gtgtgacttt catttgctag actgttttga ctatttgggg 19920 tctttgcaat tccatatgga tttcagaatt gacttttcat ttaaaaaaaa tggtagttga 19980 gattttcata ggaattatat tgaatctaca gatccctttg ggtagtattg ccatcttaac 20040 aatattgtat tccagcccat gaacatggat gtattgccat ttgtatcttt gttcttttct 20100 ttcagcaaca tttagtatat gacacttgta actccttggt taaatttatt cctaggcatt 20160 ttatcctttc tgatgctgtg taaatggcat tattttattg atttctcttt tacattgctt 20220 gttgtaggtg tatagaaata caactgatta ttgtgctttt attggattat ctgcaacttt 20280 gctgataatt tattattagc aacatttatt tattagctct agtaggtttt ttctttttct 20340 ttagagttgt ctatatatgt tgctctgtgg ataattttac ttcttgatct ccgatatgga 20400 tacctttatt tctttttctt acctaattgc tgtagctaga attttcagta taaagtatga 20460 cagaagttgt tcacagctct ccttgtcttc tctctgatct taggggtata gctttcagtc 20520 tttcaccatt aagcacagtg ttagctgtgg ggttttctta gatgcttttt aatatattaa 20580 ggatgtactc tgctatttct aattggttgt ttttattata aaatggtgtt agattttgtg 20640 actttatgtt cttcataatt gagattatca tgtggtcttc ttttcattcg attaatgtgg 20700 tatattatat gattttcata tgctgattta cctttacatt tttggggtaa accccattgt 20760 gtacacaggt tttttgaggg tctgctaatt ttcttcactc ttttctctcc ctgagacgga 20820 gtaatgttaa ctgacttatc tttaagttta ctattttttc ttctgctgct caaatctgct 20880 tgaacctata tagtgaagtt tttattttct cattgaactt ttcagcttca aaatttcttt 20940 ttggttactt tttataatat ctgtttcttt acagatattc tctatttgga aagacatttt 21000 tctcctggtt ttctttactt atttgtctgt atttttttaa agtctttgag catatttgag 21060 gcagttgatt taagtatttg tgtaccaagt ccattgcctg agcttttgca tagagatttt 21120 ctattaattt cttttttttt tttctgtgaa caggcctcat ttttttttct agaaaattgg 21180 acattttgag tattataaca acatggctat tttagaaata actctcctcc ctccttaggt 21240 tttgtttctg cttgttgcat gttgctgttg tttgctcatt agtgattttt tctaaagtat 21300 tttgaaaagt ctgttcttga tcatgtgggt ccattgaatt ctgtgttctg ttaatttcat 21360 ggtcagctag tgttttgaaa gtttcctcaa gtgcgtacag ccaataagag aaaaagaaaa 21420 gaaaaacaga aaaagagagg aaaaaaggaa gagggaaaga gattttaaaa aataatgttg 21480 gccgggcgcg gtggttcaga cctgtaatcc cagcactttg ggaggccaag gcaggctgat 21540 cacctaaggt cgggagttca ggaccagcct ggccaacatg gagaaaccct ctctctacta 21600 aaaatacaaa attagctggt gtggtggcat gtgcctgtaa tcctagctac tcgagaggct 21660 gaggtaggag aatcgcttga acccaggagg cagaggttgc agtgagccga gatcgcgcca 21720 ttgcactcga gcctaggcaa caagagcaaa actgtctcaa atacatacat aaataaataa 21780 taataataat aatgtctgct gattggctct gtttgggccc tcattcaatg cctagtcagg 21840 ccatttacaa ctctcttaac ttctactact tgcttgtgta ctgactaaag gccagctata 21900 ggtgaaagct taacctcatc tcagatctta taggtgaaag cttaacatca tctcagatct 21960 ttttggacca tgaatcctac cctgggtatg cacatgatct tcttaatttc ccagtagatg 22020 caagagtttt aataaatttt aaaagtcctt attccctcat gtatctcctt ttccgacctt 22080 ttcagtctgt ttattgttca tctgaactga catcctttgc cccaggctgc tgtggcaaaa 22140 acttttacct ttaaatgctt tcaccacaag ccacctggga agccgcccca gacctgggac 22200 tgctctgacc ctgaggaaac aaagacaaga ccttgcacag ccaggcagcc ataagacaag 22260 tccacaccca aaccccagtt ctttcagaag aaggtctgcg ttggattctc tggccctagt 22320 aaccagcaaa atactttgtc aagtattttt atcagtctgt ggttatcttg tctttctcag 22380 agcagttttt aattttaata aaatccaatt tgtcaattac ttatctcatg tgactctggt 22440 gttacatcta aaatgttatc accatacttg aggtcaccta ggttttctct aggaatcgta 22500 tagttttgcg ttttatattt ggtgtatgac acattttaag ttaacttttg tgaggttgtg 22560 aggtctgtac ctagattcat tttgttttgc atgttacttc aatattcata agaaacattg 22620 gtctataatc ttctttctta tagtatctta gccttgcttt agtttttggg caatgctggc 22680 ctcactgaat aaattcaaag tattccctct tcttcaatta tttggaaaag tttgagaaag 22740 actagtgtta actgttttct aaatttttgg tagaatttac cagtgaacca actggtccta 22800 ggcttttctc tagtaggtgg ttttgattat gctttcagtc gctttacaag ttatatatct 22860 atacagattt ttataattca gtcttggtag gttgtgggta tttaggaatc tgaccacttc 22920 atctaagtta tccaattagt tggcatacaa ttgtttatag ttctataaat aatcattttt 22980 atttctgcaa aattggtaat atcccagttt ccattttttg tttcattgaa tcttttttct 23040 tagctcatct agctaaatgt ttgccaattt tgttgatctt ttggaagaac caacctttga 23100 tttattaatt ttctctattc ttttttctgt tctttatatt atttatttcc acacgaatct 23160 ttactatttt cttcattctg ctgcccttta atgttttttt ttaatttttt atttttaagg 23220 tggaaattta ggttgagaaa tttttttaaa tgaaagcatt agagctatac attttccttc 23280 tggtgttcct ttcacttacc tgccataaat tttgataagt tgagtttttg tttgtcttgg 23340 ggtattttct aatttctctt ctaatttctt tcttgaccca ttggctattt aaatgtattt 23400 aattttttac atattgtgga tttcccagtt ttccttctgt tattgatatc tagttttatt 23460 ccattgtgat cacagaagat attttgtata atcgcagtct attaacattt attaagcctg 23520 tgtcgtggcc taacagagga tctatgttgg agaatgttcc aagtgcaatt gagaatacta 23580 ttctggtgct attaggtgaa atattctcta tacgtctgtt aagtccaatt catctatagt 23640 gttgaagttt tctgctcctc attgattttc tatcttatta ttctatccat tattaaaagt 23700 ggagtagtaa agtctcttaa ctattattgt agaactctct gtttttcaag tcccagctct 23760 gtttgctgca taagtgttta caattgttgt atctttttgg caaattgacc agtttcataa 23820 acgtaaaatg tacttcttac tgtcttctaa cagttttttt tttcttttta cataaagcct 23880 atcttttctg atcttagatt cccttacact ccaccccagc tcacttttgg ttacatttac 23940 ataatatatc ttttccatcc tttcattttc aacctgtttg tgtctttata tctaaagtga 24000 gtgtcttata gacagcataa actatgtcat ttaaaaaaat ccattttgct tatttctgcc 24060 ttttgactgg ggagtttaat ccatttgcat ttaaagtaat cactgatcat gaaatacttt 24120 cagtattttg ttaaagtttt atgtatgtct tataactctt ttgctcttca tttccttcaa 24180 tattgccttt gtgtctagct tatccttttg tgtcacactt tgatcccctt ctcatttctt 24240 tttgtatatt ttctttgtgg ttaccacgag gacaatgtat caacttttaa agttattaca 24300 attttattgt ttaaaatctc tcccattcag ggattttaga aaggttaaat aataatgtaa 24360 atgagatatc tagaacaata taagtattca ggaattagct caattccaat cctttctcca 24420 cctccacctc tttctctgtg agattataga aaagatgaca aaaaggatgt tttctgagcc 24480 ctttaattgt tgagaatgat ctttgagaaa aagaaaaaaa atgaaagcat taggattgta 24540 caacagcctg gaagtataat taagtgtaaa ttaaatagat aaaagttata agcagaggaa 24600 agtatagtag aactcagtat ttaaaagaat caatgtgaaa actatataca tttatataaa 24660 ataaaaccac cagacaaatc tgatatcctt aggatttttc tttctttcat gtgatttcta 24720 attgatacat atgacactaa accattgacc tgagctgtaa gagaaactgg aaattgttct 24780 gttatctttt gtaggatttc tagaactttt tgctctcaga cttaaatgcc aatggattcc 24840 tacttattgt ttactgcttt tggacttaca tatgatttca ttctttctca tctcttatcc 24900 ttacaatgta atttgaactg atgccaattt aagttcaatt gcatacaaaa actctattcc 24960 tatgcagctc tgccccatct aatttatgtt attgatgtca caaattacat ctttgtacat 25020 agtttacata ttaacatgga tttataaatt tttatgtatt tgtttttaaa atcctgtaga 25080 aaacaaaaag tcaacacatc aaaattaaaa taatactggt ttttatattt gtctgtgtgc 25140 ttacctttat caatgttctt tacatcttta tatgggtttg agttactgtc ttgtgtcctt 25200 taattccaac ctaaagaact ccctttagca tttctggtag ggcaggtcta gcagtaatga 25260 actctctgag tttttattta agaatgtctt aatttctagc tcctgttcaa agtaaagttt 25320 tctgtatata caattctctg tccattgatt tttgttcatt ttcctttcag ctcttttaaa 25380 tatattttcc cactttcttc tgccttccaa agtttctatt aacaaaattc agcttataat 25440 cttattgaag atctcatgta catgagtggc ttctctcttg ctgttttcaa gattctatga 25500 ctttggtttt tgatagttta aatataatgt gtcttattgt gggtcttttt ggatatatcc 25560 tagagtttct tgatcttctt agattggtat atccatgtat tttaagacgt ttgagtagtt 25620 ttcagccatt atttcttcaa acaatctctc ttctttgggg acttccattt tgcccatatt 25680 ggttcttttg atggcgtggc accagtcccc tagactctgt tcactttttt ccagtctttt 25740 atttctaatc ctcagactca atagcttcac gtgtcctgta ttcaagtttg ctgattctta 25800 cttcttccag ctcaaatctg ctgttgaacc ctcccttgta acatttttaa ttccattttt 25860 gtatttttca agttaagtat ttttattagg ttcctcttta taatttctct ttgttgatat 25920 tctcatttta tcacacacaa tttgtctgat ttccattagt ttttttcttt gttttccttt 25980 agctctttga acatatttaa gaccttttta aagtctttat ccaagttcta tttctgtgct 26040 tctgtggaga tattttctgc cagtttatgt tcttcttttc catgggccat gttttcctgt 26100 ttctttgtat actttctaat tttgggttga aaactgagca tttgaaaata gagccaactt 26160 cccagtttcc acagcgagtc tttatgccac agtatgcttt cactgattaa ttaggtatat 26220 ctaagcttag ggagcagctg agtcaaaagt ttaaggtctt ctcaggtctt ttctgaatat 26280 acatgtttcc tatgcctgtg tgaaacgttc tcaatttccc tatataaaca gctttttttt 26340 tttttttttt ttttttgaga cggggtcccg ctctgtcacc caggctggag tgcagtcatc 26400 tcggctcact gcatcctcca cctcccgggt tcaagcgatt ctcctataca gatgtgtgcc 26460 accacatctg gctaattttt gtatttttag tagagacggg gttttgccgt gttggccagg 26520 ctggtcttga acgcctgacc tcaggaggat tacaggcttg agccacagcg cccagcctaa 26580 acagctactt ttgaatgcct taatttcctg aatagtctca acccagtttc tccttgaggt 26640 cttaggtggt ccattgtgtg tctccaccca tagtcgcttg ccccaggcat ctgtgggtct 26700 gtggtaccac tgcagctttc accacccgta gctgccactt tttcccatct gagatcccag 26760 ttaggtgaga gaggtcattc cttcacgcag ccccttgaca ggttagaaca tttcaaataa 26820 ggtctgttct gctcctctgg ttgaagggag agaactggaa accagtttcc caccttctac 26880 aaaccaagat ctcatggtgc cacgggagtg gcaggacaag tgcaagtgaa aatgccatac 26940 aattttctac cattttgaac gcgggttttt cttcattggg catttgcttg gttgctgtag 27000 gcttttcagt tttccagagc tcacacaaga ttactttagc tggttttttg ttctttcctg 27060 atgcttccct ggcagaataa gggttggaat ttccaccatt ttgctgattc ataactctgt 27120 agtcagtttt aaatatactg atacttgagt ttgttttatg gcccagaatg tggtcttggt 27180 aaatatttca tgtatactca gaaagaatgt gtattctgat gttgttacct gggctattct 27240 ataaatgtta cttaaggtgg ttaataatgt tgctcaagtt ttctatagtc ttgctgattt 27300 tcggtacatt cattccacca atgactaaaa caggtgtatc aataaaatct gttccatcag 27360 gttttgcttc aggtattttg agggtctgtt attaggtgca taaacaagat ggttatgtcc 27420 tattcttaaa ttagcctctt tatcattatg aagttaactt ttttgtttgt tttttgagac 27480 agagtctcgc tctgttgccc aggctggagt gcagtggcgc aatctcggct caatgtaacc 27540 tccgcctcct ggtggttcaa gcaattcttt gcctcagcct cctaagtagc tggggttaca 27600 ggtgcctgcc accatgcccg gctaattttt ttgtattttt agtagagatg gggtttcacc 27660 atcttggcaa ggctggtctt gaactcctga actcttgatc cacccacctc ggactcccaa 27720 agtggtggga ttacaggcgt gagccgccgt gcccagcctg aaataaactt cttagccctt 27780 gctaatgttc tttgctctga agcatgcttt gctggtatta atatagtcat tcctgctttc 27840 tttgattcat gttcgcaggg tatatctgtt tccattcttt tacttttaac ctattgtctt 27900 tatatttaaa gtgcatttct tgtaagtata attggtttct caaaatccag tctgacattc 27960 tctgcctttt acatgtcatt tttatatgat ttgtgtaaat atgattatta ttacagctaa 28020 attgaagtct gtcatcttgc tatttggttt ctatttatcc catttttccc tttttttttt 28080 tttttttttt ttttgctttt cttgagattg agcattgtat tagttttcta gggttgctgt 28140 aggaaagtga cataaactgg atggcttaaa acaacagaaa tttattgttt cagtttggag 28200 gctagtcatc tgaaaccaag gtgtcatcag ggccatattc tctctgaaac ctgtaaggaa 28260 gaattctttc ctgcctgttc tagcttctag cattttccag caattcttgg cattctgttg 28320 cttgtagatg catccctcca atctctgcct ctatcataac ataaccatct cctccctttg 28380 tctgtctgtt cttctcatct tataagaaca ttaattgctg aactggggcc cagcatagat 28440 taggcctaat ctcatcttga ataggttata tctgaaaaat tcttttttca aataagatca 28500 catttatagg tactaagagt tagaacctca atatatcctt tggcggggac caaactcaac 28560 ccataaaaag tattttatat gattccattt tatctcctcg ttaggttatt aactatatct 28620 atatctatct atctatctat ctatcttttt tttttttttt aatttcagat ggaattttgc 28680 tcttgtagcc caggctggag tgcaatggca cgatcttggt tcactgaaac ctctgcctcc 28740 caggtttaag tgattgtcct gcctcagcct cccgagtagc tgggattaca ggcatgggcc 28800 accgcgcctg gctacttttt gtatttttag tagaaacagc gtttcaccat gttggctagg 28860 gcaggtctca aattcctgac ctcaggtgat ccacccacct cagcctccca aagtgctgag 28920 agccgccaca cccagcctta taattctttt ttaattcagt ggttgcttta gggtttatag 28980 tatacatctt tatcacagtc tagcgccaag tgatataccc ctttatgtat agtacacggc 29040 ccttacaata gtgcatttcc atttttcctc tctggcattt aggccattgc acacacataa 29100 actcaattga tccctttgtg tagatccgta tttccacctg ctatattttg cttctgtctg 29160 aaatctatgt atgatttctt ttatgactat tttgagcaat ttggttatgt tcatttgcct 29220 atttttctta tacactttta gctcatcaat cttaactctg tgagtttata gtttttaaaa 29280 acaaatttga aattatttgg ctattatttc ctcaaatact tttttctgcc acccctgctt 29340 tccctttcct tagggatctc cgatttccac ctatattagt ctgattgaag ttgttccaca 29400 tctcttttga aaatctctgg aaaatctttt atcattggga taatctgtat ttgtacatct 29460 tcaagtacat taatgtttaa tctgctgtta atcccatgca atggattctt catctcaggt 29520 attgccgttg taatctctag aagttccatt gaagtcttac ttgatgaaaa atgtggataa 29580 aaacaagtgg tggtaaagat atggagaaat cagaatccgc acacactgat gatgggaatg 29640 taaaatggtc aaggcaattt ggaaagcagt ctggcagttt ctcaaaaggc taaacgtagt 29700 taccatatga catagcaatt attcacctag gtatatactc cagagaaata aaaccttttc 29760 cacaccaaaa cttgaacatt acttaatgtt cattaggggt ttaaaatttt gtacagtatt 29820 tttatttaaa gtagagatgg gggtctcact atgttgcaca ggctggtctg gaactcctgg 29880 gattaagcgt tgggacctgc cttggtcctg ttttctccgc tggaagagaa taaaactttg 29940 tacgcttgga ccaacaactc ccgattccct cctttaccac catgccccat agcctctagt 30000 aacacttact gtccacttcc atgaattcaa ctttttaaag attccacata taggtgagat 30060 cacgcaatat ttttctgtgc ctggcttatt tcagttagca taatgtcctc cagattcata 30120 agtgttatct caaacgacag gttttaccct cctttaaagg ctgactagtg ctccattgtg 30180 tgtatgtatc acattttctt tatccattta tctgttgatg ggcacttaga ttatttcaat 30240 gtcttggcta ctgtgagtaa tgcttcaata aatatgggaa tgaggatatc ccttcaacat 30300 attgatttct gttcttttgg ataatactca gaagtgagat tactggatca tatggctgtt 30360 ctattttttt tgagaaacct ccatactgtt tttcctaacg gctgtactaa tttacattcc 30420 cactaacaat gcatgagttt gcttttctgt acatcctccc caacactcgt catctttcat 30480 ctttttgata aaagccatta tataataggt gtgaagtgac atctcactgt ggttttgatt 30540 tgcatttctc taataattag tgtgagcatt ttttttttta aatgtaccta ttatcatttg 30600 aatgtctttt gagaaaggtc tcttcattcc tttgcccatt tcaaaatcag gtggttttct 30660 tgctcttgag ttgtttgatt tccttatgta ttttggatat ttacccattt ccagatgtat 30720 catttatatt tttttcccat tctttgagtt ctctcttcac tgtgttgttt ccattgctgt 30780 gcaggtcttt tattttgatg ccacctcatt tctctatttt tgccctgctt ttgcagtcac 30840 atccaaaaaa atcattccta agaccaagtt gtggagattt ccccgtatgt tttcttcagt 30900 aggtgtacag ttttaggtct tatatgttaa gttttaaatc tattttgagt tttttttaat 30960 atggtgtaaa caagggtcta atttaattct tctgcatgtg gatatccagt tttcccaaca 31020 ccatttattg aagaacctgt cctttcccta ttgtgggttc ttggcgcttc tgtcaaaaat 31080 cagttgacta taaatgtatg actttatttt tggattttct attctattct attggttgat 31140 gtctgttttt atgccagcac catgctgttt aattataatt agtttatgtt tttaagtcaa 31200 ggagtgtgat atattcagat ttgttctttt tgctcaaagt tgttttggct atatacggtc 31260 tttttgtggg tccatatgaa tttaaaaatt gttttttaca tttttgaaaa aaaatgacat 31320 tgtcatttca aagacattgc attacatctg tagattgcct tgggttgtat aaagatcttc 31380 ctaataattc ttctaataca tgaacatggg atatctttcc atttatttgt tttctttcat 31440 ttcttttatg ttttatagtt ttcagtatgc agatctttta cctccttaaa tttacacctc 31500 agtatttaat agttgttgct attgtgagat tttcataatt tccttttcac atagctcatt 31560 aatagtagat ggaaacacta ctgatttctg taagatgatt ttgtattacg caactttact 31620 gaatttgtgt atcagttcta ccaggtttta gttttgttct ggtggagaca ttacagtttt 31680 ctgtatatgg ttatgtcatc agtaattaca gatgatttaa cttcttcctt tcctattagg 31740 atgcctttta tttctttctc ttgtctaact gctctggtta ggacttctag tactatgtca 31800 aaaagtgatg agggtcagac atggcctcca tacctaatct gttgagagtt tttaccatga 31860 gaccaggttg aattttgtca aatgcttttt cttcttccat tgaggtgatc atatgatttg 31920 atttacaccc ttcattttgt tatgtggtgt atcacattta ttggtgtgca catgttgaac 31980 catccttgca tcctaaggat aaatcccact tcatcatggt gaatcattct ttgtgttcgt 32040 gaatccagtt tgctaatatt tgttgaggat ttttgcatcc atgttcatca gggatattac 32100 tttgtaagtt tctgtccttg aagtgtcttt gtctggcttt aataacagtg caacactact 32160 cttgtaaaat aagtttagaa atattccctc tgcttcattg ttttggaaaa gtttgagaat 32220 ttgtattagt tctataaatg tctggtaaaa ttcagtagtg aagctgccta atcttgggct 32280 ttcctttggt gggatgtttt tattactggc ttaatctctt ttcttattat tggcttattc 32340 agatcttgtt tcttcgtgat tcactatttg taggttgtat ataactagga atttattcct 32400 ttctttaggg tagtgcataa cttcatagta gtttcttata atcctttgta ttttggtgat 32460 atcagttgta aatgtcccct ctttcacttc tgatcttatt tgagtactct cttttttccc 32520 tagtctaggt aagaatttgt ttttatcttc cccatccccc ccccaaaaaa accccacaat 32580 ttttagtttt gttcattttt tctagtcttt atttcaactg tgatctttgt tatttacttc 32640 tttatgctaa cttttgggct tagtctgttc tttttttagt tcctttaggt gaaaagtaag 32700 attatttgtg atccttcttt gtcgatgtag gtgtgtattg ctgtaaattt ccattaggac 32760 tgattttgct gcatcacata agttttgttt ccattttcat ttgtctcaag gtaatttttt 32820 atttactttt tgatttcttc tgtgaactat tagttgtttg ggagcatgtt gtttaatttc 32880 cacatattgc tgtattttcc accagaattg attcttgttc ttgatttcta gtttcatgcc 32940 attgtaatca gaaaagggac ttgatatgat ttctgtcctc ttaaacctaa gaatagtttt 33000 tggactaaca tataatatat cctggagaat gttccatgtg catttgagaa caaaatgtat 33060 tctactgctt ctggatggaa tgtttcatat atgcctgtta ggtccatttg gtctaaagtg 33120 taattgaagc ccattgtttc ttaatattga ttttctgtct agggaatcaa tctgcccact 33180 gtgaaaagta gagtattgag gtcctatctc cctcttcaga tcatttaaca attgctttat 33240 gtattcaggt gtgtcaatgt tgggtgcata tatttttaca attgttatgt cttcttggtg 33300 aattaatccc ttatcattat ataataaact ttatttcttt ttatagtatt gacttaaagt 33360 ctattttgtc tgatagaagt atagttaccc ctgctctcaa tttccattta ggtagaatat 33420 ctttttccat cccttcacct tcagtctatg tgtatgttta gtagaaaagt gaatctcttg 33480 ccgggcacag tggctcacgc ctataatccc agcactttgg gaggtcaacg cgggtgggat 33540 caccagagat cgggagttcc agaccagcct gaccaacatg gagaaaaccc gtgtctacta 33600 aaagtacaaa attagctggg tgtggttgtg ggtgcttgta atcccaatta cttgggaggc 33660 tgaggcagga gaattgcttg aacccgggag gcggaggttg cagtgagaca agattgtgcc 33720 attacactcc agcctgggca acaagagcaa aagtctgtct caaaaagaaa aaaaagaaaa 33780 aaaaaaaaaa ggaaaagaaa aaaaaagtga gtctcttata ggtagtatgt ggttgtgatt 33840 taaaaaaaaa aaaaaatcca ttctgtcatt ctatgtcttt ttcttggaga atctaatccg 33900 tttacattca aggtaactat tggtaagaaa tggctagtgt cattttgtaa tttgttttct 33960 gattgttttc tagctccctt gtttcttttt tccctactgc taccttcctt tgtggtttgg 34020 tggttttctg tggtggtgtg ctttgaattc tttcttttat agtctatgca actaccgttg 34080 tatttgccat aaggctaact taaaacattt tatccttata acaggatact ttaagcagat 34140 aaaaacttgc ctttagttgc atacaaaaac tctatgcttt cacaaccccc caccttttat 34200 gattttgatg tcaaagttta catttgtttt ttaaaatttg tatctcttga caatttattg 34260 tagctacagc tgtttttgtg tcatctttta aacctaatac aaataacatt gctttacctg 34320 ccacttttac catagtagag aattctatga atgacttata ccatttagtt ttttactttt 34380 atgtttttcg ttaactagca gtcttttatt taagcctaaa gaactccctt tcagtaattt 34440 cggtagagca ggcctagtgg tgacaaactc ccttaggcat tgtttatctg gaaaagtgtt 34500 tatttctccc tttgccaagt aaagtgttgt taattaacag ttttgtttct ttcagcactt 34560 tgaatatacc atcccactct cactggcctg taagactttt tgctgataaa gccactgaat 34620 ctgtattggg gctaccttga atgtgatatg tttcttatct ttgctgcttt cagtattctt 34680 tgtctttgat ttttgataat ttggttgtga tgtgttttgg tgaactcttt gggttgaatt 34740 tggtgacctc agcttcctgt tactgaattt tgtcatcttt tctcagattt gggaattttt 34800 cagctattcc ttccttatat atgctttcta ggcctttttc tttcttttct cgttaaggac 34860 ctcctattat gcaaaagtta gctagcctga tgtgtcctat aattcttaca ggcattcttt 34920 tttgtttgtt tctcattgga taatttcaaa tgtcttacct ttgagctcac tgattcttct 34980 gcttgatcaa gtctgctgtt aaagtgttct actgagattt tcagttcagt tactgtatcc 35040 tttatcttta gaatttctat tgtttgtgtt tatatttctt tgttaaactt ctcattctgt 35100 tcatacgttg ttttccaaat ttcatttttc tgtccatatt ttcttgtact ttgttgaact 35160 ttaagaggat tagtctacat tatttgtcat ttcacagatc tctatttctt ctgagtctgt 35220 tactggagct tcgatatcca atgtacacca gaaactttgc taattccata gtaaatgtta 35280 gaaatgggtt ttttaatggt aaaatcagtg gcttgctaat ttgtatatta gaagctggct 35340 tgcattggtg aagttgaggg cattcgatat atgtatcctg gctaaaatac ttctagagaa 35400 cctctccacg ttgcaagaat agggtataga aatctgagga ggcctttaac atggccctca 35460 gaaaggacac acagggcttg acccctaaac atataaacat gtacagaaat gaggtgagaa 35520 catgttttga ctgatgccag tagttaacac agcagagcct aatgctggtc actgttacaa 35580 ataccttgta taataaacct ttaatttgag aggctgtaag ccctgaaagc aaagggctta 35640 tagtacctct tgcatgaaca ctcctgtgtg tgctttctaa gaaatgcttt aaaaataatg 35700 catgtggcac aacttgattt gacactggct ctttataagc tgctatcaag gttgtgggga 35760 atagctaact cctacccact ttccctgaca aatagaaact ggtagttacc taccaaaagt 35820 atgtaaaagc tgtatctgac ccaaaggcca gttaggtcaa aacaccttga aaggagctca 35880 gtttaaggaa atcagtggtg tcacagagcc ccactaacgt gtgtacaagt tttcatagtt 35940 tgactatagg atgtgcttag tttcacaggt gagtcttacc ttgtgatact tttagagcaa 36000 aagtcaaatc aaagatgatt ttaaaaaaac atttcaaaga atcataaaga ataaatgcct 36060 ccttaggaag tcttctggag ttctgcccac ttcccttagg tggctcttta ctgtgcccat 36120 ctcatagctt ctctccctgc atttggtgta ttgcagagta aagctcactg tttacaggag 36180 tggtagaaag tgtggtcctt tcccggactc ctttttccct tccccttctc gtttctggga 36240 atatgtgttt gataatagaa ttaaacaaca gactgacaaa tgactaacac atttagctaa 36300 gctacataag cagacgtcag tttgacgtga agggtttaaa atatctatga attctctggg 36360 gactcctccc ccagacctga aggatcaggt gctgccttct atgccacctg tgcagagggc 36420 aaaagaggaa aaccatactc atgttcagtg tgagtaaagg ggacatttga actctgtgca 36480 gacccctcat tggaagggtg tttcttctcc tgctgcatcc acaaagagca ctccttagcc 36540 ttgccttttg tcagttctct ccccaataag gttctgagca gagaacccag tgcagttcag 36600 agactgaagt ctggtgtccc aggtctgagt tctagctcta gctctctgtg taactttggc 36660 atgtcccaaa gtaactttcc acaacttgac aggtgttact tgagttttgg atacaggtga 36720 ctcttagccc atctgtgcct cagagatgtc atcacttggg ccacatgacc tctggacacc 36780 tttcctactt tgagcggcag aacagatggg agctcctgct gcctctgagc ttcagtgaat 36840 tatcacttgt tggagggaag cttcaagcat tttgtatctt ttgtatcttt caagagcaag 36900 cacagtcagc aagaatatgt agcagatgct agtgaacacc agtgattagg gttgaatgct 36960 ggatttaaat atggagctta ggctgtgaag gaagcctgaa gaacctagag ccccacaaat 37020 tgctctctgt gagatctgac accatttccc actgatgagc cttgggtcta ataggtagca 37080 ctgattccac atagagtatg tgagtgtaat acactgaaag caaagagaat aaaatgatgg 37140 ctaacatgat gttccaaact ttaaacagga gaaaaacaca taattccatt atgtataaga 37200 acccacacag agatcaggag aataacctca ttggagaatc aatgacctat gtggggaatt 37260 tagggtagag ctgagattga aaaaatgggc caaagccagg tggccaaggg ccttaatacc 37320 ttgtatacaa gatgtgtagt caagaaagac catgccttag ttacgcagca attcccttgg 37380 gcctacaaag agctgcctag cctgggacta ttgtagagaa aggctactat gttccagtga 37440 tgcagggact cctccatata tatatgcgtg ctcagttggc tctgtaatac atcttacttt 37500 tatttattaa cttttcttgc acattggctt ggtgcatcag ttggaagtca gaggctgaac 37560 gaagtgaaga ttgagccaaa ggaagttctc agcctttagg gaggtggaat tcacattaaa 37620 cacacaataa acaaatgaac tcacattata aaggagagag tcagaagatc ctagtggctg 37680 gtgtcatcgg gccttatttg cccgaagtgc ctattcttta taggaatcca ctcccagggt 37740 agatgggcta catccttagt aggctttatg cctatgttct cctggccatt gcctcctcca 37800 gggctggcct ttttcagtct ctctgtagag gttcctgtgg ctggttggat ataggccttc 37860 acagaagggt cagtgccttg gctcaggtta caggactggt aatcttgctt tgttaagagt 37920 aatgttattt ccccatttcc aaattctcca gggagatgga atgtcaaaga tagtatcact 37980 gtagcaccta catcctaggt tccagaagca gagaagagaa tatactgaag ctgtagaaag 38040 gcctattagt ctgtgtcaga gattaactgg atgtgaggac catttctggg atggtgtata 38100 cagaactgga gaactggata gggagtcaga aagagctgaa gacgatgtct ttgaagtttc 38160 caaagtggat aactaggtca acagtgtatt attcaagaaa gtattaacat aggattgaga 38220 tgcagtcagt agtcatggaa ttgaaatttc aaagtatata cctcttggat ctcaggggtg 38280 ttgagctgat cacctgggct aacactccta tgaccctagg gaaaatcaaa cagcctggtc 38340 ctgtggccat ggtaggggtg tcatcacctt aatcaaactg ggacagtgct gttggatatt 38400 catctggaac ttgttgcaga cccacatttt gctgggtttc accacaacca aggccttttt 38460 gatccttttc tcggttaaca tcagtacatc attgcaaagt taatcctcat ataataggga 38520 atgaaactaa ttgcttataa aaacaagatt tttacaactc taaaattgtt caagcatacg 38580 ggcatattta tagttgcagg cagtgtttca ggtgcagact gttcttggct gcagtggtgg 38640 tttacagaca gcatctgttc aatatttgat gattatcccc gaatgtttta aagcgtagta 38700 ctgggctctg ctgaccgtac aacaaactgg catttttgac ctatagggcc ctgggctagg 38760 agatacagtt ctgaggggaa gtgaaagaca gtgaacaact gcacaactga ccctttgtta 38820 gttgcaataa agcaatccaa ccacccaacc cactctgatg gctttcctac tatttaaggt 38880 tggtgatgtc aaagagacac cctcctgttc agtgtgcagt gagtcaacat catttccaca 38940 aaacctcctt cctgcacaaa ggacttatca tagttggtta agaagtaaaa ttttcctgta 39000 tcagtcacag gagttcacca gttaagatac tgttagctga agacttctgg ggtgacttaa 39060 tgaaatagct cagccatgtg gtttaaaaac gagattcttc catccctcca cacagctgtc 39120 catgcatctg catcatgtca aggctggtct ccttggtggt agaaaggctg acagtaaaaa 39180 ctggagccac atgattcctt gcttaggcac agtgtttctt catactctca catgggagca 39240 ggcatgttct ttccccaggc tcacagtaaa cactctgtca aatttcacag gcccaaagtg 39300 cttttggtta tccccattcc aaaccaattt gtggcaggaa agcattaccc tgactgcctt 39360 agactaatat acctactgca cttctagggc tggggataat tttgaggtca accattcaaa 39420 ctgcacggca gtcattccat ggaagaagta tggtctaaat ctttggggca acctgaattc 39480 atgaaaactc tcttagattt atgtaactaa ttttagaatt cacttctgta ccatttaatt 39540 ttactaataa aaatactacc tttaccctaa atttcagcca agcgtaaggc tcccttggga 39600 cagaaggaat tatcaaagct ttgtgttttt atacatagta gcgtttgaca aagaaataac 39660 tctgaaggaa ggagaacaac caagcagagt ctagatgcac agaagtcttt gaggcttggt 39720 aggcagaagg aaagggcagg actacttcag gaatacaatg tttcagtaac agaggttggg 39780 gtctgttgat cttgaggaga gatgaggatg gactggaaaa taggagtgag atagtaggag 39840 aggaaaggag atggatggtg tatatactgt atggctaacc atcaatcgac cctaagaaga 39900 taatagttgt tagatggtta gctatttaaa gaaagaaacc tgaacaagta acaatcttga 39960 gttgcaaagt ggctggagtc acacaacaga ctaaatttct ggtagaacaa atgcagcagc 40020 ttatgtgaag attaccatgt ctgaagctgg ttagaaaagg tctaacatcc aaccaaagtc 40080 acagttcttg agctcggtac acagagacag actgctaaca gctgatgtgt cctcagcgag 40140 agtgtcctca tttatatcct cattctcctc ttctgcctcc ttttttgttt gtttgtttta 40200 aacctttgga aagtctcatc attcaataca gtctaatata tcacaataac agaggcggcc 40260 caatttctac agattgacta attccatcct tgaaaagttc atataataaa actatataaa 40320 gcatcatttt caaccatcct ttagaaaaat tcccctatta aatgttaact ctaaatcctt 40380 tatctctgtt aataacctta ctaaaaactt ccccatcact gcctgccagg gagatcaaaa 40440 gaaatcacat ttacgaaacc tccaacacct gtacctgact gaaaagcaaa catacagacc 40500 tttcagtcct gccctactat tccgctccta tcacacagag gcacgtggac atctccttgg 40560 gaagcggaca gctcttaggt ggaagctagg cctgcagtaa gcaggccagg aaacatgtct 40620 cccaggaccc acactcttgg gagaagcacc tggccaccag acagcatgtc ctgtcaacct 40680 acagagttct gaaaaacaaa cactggaccg ggaatagaac cctgtggtca cagtgcccac 40740 agttcactaa gcaccctcac aggtctttga cagaacactg actgccaggt cccctcgtgg 40800 gcagagaaat ggaagattcc caggcccaac tgagcatctc agggaagaac cacaagcaga 40860 gcaactgcca gagctggtcg gctagcgttg gcaaccaggg aagcaagtgc tacaccatat 40920 ttggagagag cataaaactt aaggaaatag agaagtccta ctcaattctg ttcttcaact 40980 ggaaacgaga acttgcgaaa aagaaaccca gttttctgga gtccatggag aaatatgaag 41040 ccaatgctcg actaacagag cagaaagcct tttataaata atgccagtca aagctccaaa 41100 ggtcagagct gatgcaagcc tgactgttct gacaatttcc taggttgcta ggcaacaagg 41160 agctggtcaa acagctcacc ttcgaggacg tactttataa taccaccctg gtagacgagc 41220 gcgaggcagc agtgaaggca gtagtcaaga acaggagagg gaggttaaca gcaagatgct 41280 cttcagacag tctggacaaa gacagtctct acccagctct caggagtggc ctgcttaaga 41340 aggtggaggc ccaggcagct cccagggtga ccctaaagac agactccaag gaaaagggtg 41400 tgagggcaat ggtgaatagg aggaggtccc agtagacaca gcaagtcagc tcaggtttta 41460 tctttagagt ctctgaacta aagataagtg aagagaagcc ttctgtggac agcattccag 41520 cactatggga ggggaaaggt gccacgagag acttctccag tggggcacac aagcattgtg 41580 cagtgatcct caagatccag ccattggcag gaaatcgaaa ggcaagcttc ttaattacat 41640 agtctatgga gacagaagtg tggtgcaccc ccaaaataaa aggccaagac ccaggaacaa 41700 cctccacaac ctggagtata tacaaatgaa cccaggcctg ctgactcaga tccacgccat 41760 cctaaagcag ggtattctca cgaatgaaag ggctgagtat ttggtgtaga gaatcagaag 41820 tctcccactg cccacacatt ttctcttcaa agatttcttt tccaagaacc cattgaataa 41880 agggagggag ggagcactga atgccccaga catcagaatg catgatgcag gaagaggaca 41940 gtaaatagtt ctcaaagaga tcagaaaata aattggaagc aatttcatta ccacaaataa 42000 tagacctttt ttctaaggca ccccttccct ttccacccaa ttgtcattca gcaactactg 42060 aatacttacc aatgaaaaac cttacccctg acctcaaggc tgctcctgag ctctggtaga 42120 aaatgctttc ctcatctata aaacatggca agcaaggcag gatttaatag taagaaagag 42180 aactcagggc acagtagcac tgcaggactt caaatggaaa tatggagaca agcagtgaga 42240 acaggcagca aaagcagggc aggtgaggct gggaccaggg catctggaac tttccacacc 42300 agcttggatc tccatgccaa acaacagttt tcaaggaaag gtatctaaga ggaacatgac 42360 tctgggaaac tttttggcag tattgcttac tgcatactag aaagtaaaag aatttgggga 42420 acattcacta atttgcttct tcaggggctt gggtagggaa caggaacagg aacctggctc 42480 taatttctga acttttatca gtaaaaacaa tccaacaaat gaaagttagt caatgagaga 42540 actgggaggg tctgccctcc ctcctccttc cttgagtcaa gccttcttgg gggggacctc 42600 ctgacattta attaagtgaa ggcaatgtcc actgaaggaa gcggacctga aagtgacacg 42660 ctactgtgaa atgagcatgg agtaggagct tgttacatat atgaaatggc cagtgctctt 42720 gagcaaagcg cttcacaact tgagacctaa gttttctcct ccatatgctg agggctgggc 42780 aagatgatct gtcaggccat ttttacccct aagccaccaa aatccaattg ctttagcttg 42840 tcacaaaagc aggtatcgaa tggctatcct gcagtccctc cagtcaacat ccagactttt 42900 tccctgaggc aatataagac aacagttaac atatttttat cagtttaggt ggtcatgaga 42960 taaacatatg ggaggtggta gtttttcact taaatgaata taataatggt acagatctct 43020 ttgagtagta tttgtttctt aaatatttaa gttccctaaa gacggtaaga ataacccaag 43080 aaagtgaaat taatgtcaca aagcacatgg ctaaataact gcaggtttgc agtgccatgt 43140 gtgagatcag atgacagaag ggaggcctac cttcaggcag aggcttctca tgttccctgg 43200 agtggccatg tgctcttcta cacgactgct tccacttcgg ttacgtagaa gctatttaaa 43260 gcacacagat ggttgtgatg agataaaagc cacccttaag tgaataatgg aaattaaagc 43320 atgatttgag ggtgggggtg gaggtgggag tagagatggg tagaaaggag tgcaagggaa 43380 acaaaggagc cttcataaca ttaaagtcac ttaggataac atgattgatt tactcaacac 43440 cttcttagga acataaagca aacaagtggg ttttcctttt actgcttttc tgaaatgagc 43500 tacactcaag aaagcaacat gggggttgtg ctgtccctgc acagtggcag gagaatatga 43560 ggagcagctg aatgccagaa cagctccatc caagatcatt tttcacacgc atgaaccatt 43620 cttatactac cttttactgg caatttctgt agaaatctgg aagtctggtt gacaaatcag 43680 gcccttgaac tttgcaatca cggtggcatt catatattca ttcagcaagt atgtgtgtac 43740 gggacagtgg agcaaataaa acagatacgt tcctactgtc atgaggctta acatttaagg 43800 agggaattag gcagtcatga agtaaacata aaaatacaga ttgtaatagg cactatggaa 43860 taatgaataa tttggggaac acaatttaaa tttgaaatat atctcagttc cattaacaca 43920 tgttgaaggt gaatggcatg gcactttttt gctggattta gggcctggat gcaagcatat 43980 tggggtaact tctgaaatgc atcgtagggt aatgcatttc ctcccatttg ggcccaagtg 44040 tattatttac cacccagttg tgatgagctg ggatcctcct gctcaatctc agcttgaagc 44100 acttggaggt tacctgcctg ctgtgggtga ttattttgga gcaaggtact tcatttgcct 44160 caagaaacag atttgatacc actactgtcc ccttttggaa cagagaagta ggcaagaccc 44220 cagtgtgagg cagagtgatg ggatctttag gatgccagag tcattacatc attatgtaat 44280 gtatgtaatt gatgtaactg atgattttgg agtttatata tttccaaagt ttcaaaatat 44340 tttcacttgg ctgatttatc tttatggtga tgacagtaag tagatatatg ccctccttaa 44400 aagttacagt gagagttgac attgggaaaa gggaggcttg gccagggtta tgcagacaca 44460 gtacggagga ggatggaaag tttctgagac accccagtta actgcgtgga tccacaaagc 44520 acatgtacag tctgctctgt gcactggagg tacagccacg aaaaagacag tctctgccct 44580 catggagctt ggtgtctgtc tactgtagca gacaaaaaca aacctgctgt ttctcatttg 44640 cctctgctgt gggttccctg tgtaactctc aaatgctagc atttccatgg atccttgtcc 44700 ttctctcctc tctgcctttt ccaggatgag aattttcctg gccacgggtt cagctatggt 44760 ctatgtgcta gagtcataca tttttatttc tgtgcacatt tttctctaga cccgtatttt 44820 taactgcctc aggacagctc tccctcgata tccctcagac acaactcaaa cgtcattcaa 44880 ttctactatt aatacttttc ccttcaaaac ccactcttct tctgtagacc caacagcaac 44940 actgtccacc cagctctcaa aacctgaaat gggggagctg tctttgactc aactctccca 45000 tgcatgagca ctgaatcaat caccgagtcc ctagcatgtc ttggactctg gcctcccttc 45060 tatcctcaga ttgtctgcct tttaaaaatt atagcaataa cttaactgca aagaccacat 45120 gtacacttgt gctctttcag tttgcaataa acataaaatg taaaactgat tgtctttgct 45180 tcttagcatc tgcaaaataa agtccaaagt ccttggtatg gtctgtaagg ccctcattat 45240 cccaatctca tcttgattcc ttacagcctg cactcagata tactaaagag cgtccgcctg 45300 tctgcctcac acacacctat cctgtctgtc aagattcggc ttgaccttca tcacctatct 45360 gcagtatttt tggatttgaa ttctctgccc acattgtact ttcacatact tcttttatcc 45420 ttagtggttt gtacttatgc ctgctctaac tagactgtct ccctgtagta gactccttga 45480 ttcaacaaag cagctctcca tcagcctgaa atccgtggca cccggcaaaa tggcaaacat 45540 gcaataggta tttgctcagt aaatgttaat gaaaggaaaa aaattcaaac ttcagttgga 45600 ataggattag agacaactta aaaagtttcc catagaaatc ttcctcatca taaatatcat 45660 catcctcaat gtcccgagtc tttccacagg tctgatttac caaatgagga agactctttc 45720 tcactgtgtg tgtgggagag gcaggcgcag aacatgtttt tttttctgca agtctgctct 45780 ctggattcat ttttctgggg atgaaatctc aggctgtgta gcttttctgg tccctttttg 45840 gtaatcaaca aatcatcagt tgttctaggg tattaaaaag cccacacctt tgaaacatca 45900 agatgccaaa ctctctctta atggaaaaca taattccgcc tcttactgag gcctttgagt 45960 gggaagctta aagacagcag tgtggggaaa tcggtttttc ttttcctccc tccaccttct 46020 ttcccattca agagctgctg ctgccctttc tggaggggag ggaattagaa gaaaagatcc 46080 tgccttaccc agtcactgtt aattattact ctgagccagg gtggtgaatg actctttcct 46140 ggaatacacg ctgctgggaa ccaccgctga gattctctaa gcaggcagct tccaacctct 46200 cctccctcaa cagcttcaac attatatggc actcagctgc agggtgcctg gctccaggca 46260 ggcagcccac ttgtgcaggg tagttttcca gatggctcat agtccatctc ttttcagtga 46320 ccagtgtggc ccctgggaaa catacgtctt gactccatta ttggtgggag tactctttag 46380 ttagttgcca caggccactt cagacatgtc ttaccctgag acccttttca gagtcaggta 46440 ccatccctct gtctcctagc atctaaagat cacagctgaa ggtctccaag tagttcactt 46500 aaaaaatacc tcagtaggtg taagaacagg gaaagccccc aattcattct gagagctgta 46560 tgactctcat ccccaaacca gacagatata taatatgaaa actacagacc aatattcctt 46620 atgaatatac atgcaaacat tctaaacaaa atactagcaa accaaatcta gcagcagaga 46680 acaaggttta tgtagcatgg acaactgaga ttatcccagg aatgcaaggt taattcaata 46740 tacaaaagtc cattaataca acatattaat agaataaagg acaaaacaac atgacaatct 46800 tgatacaaaa gaagcatctg acaaaatcca tagcccctct tttttttttt ttttaattaa 46860 aaaacagtaa actaggttta atagaagaat ttcctcaact tgatgcaaac ccacagctaa 46920 catcatactc aatgctgaaa gactgaatgc tttcccccta aatcaggaac aagaaaaaga 46980 tgtctgctct tgtcacttct atccaatact gtactggagg tgccagccag tacactaaga 47040 caagaaaatg aaataataag aatctagact ggaaaggaag aaggtatttc tgttcacaga 47100 tgcatgatct cataagcaaa aaatactaag tgaccaaaaa aatagaattt tagaaaagct 47160 acaatacaca tgatcaacat acaaaaatca attttattac taagaccagt gatgaataca 47220 aaaataaaaa ttagaaaata atcatataaa gtggcatcaa taaaatactt agaaaaaaat 47280 taaagaagtc aagacttgta cactgaaatc tataaaacat cactgaaata aactaaagac 47340 ctaagcaaat gcaaagacat cccacagtca tggaatagaa aacctaatac cattaaaata 47400 gcagttattt ctcaaatcaa ttcaactaaa tccctatcaa gatcccagct ttgcaggaat 47460 tgacacaatg atcctaaaat tcgtatgaaa tgcaagggac tgaaaataga caaatgattt 47520 tggggaaaaa aaaactggca gacttgcaca tcccaaatcc aaacttagta caaagctaca 47580 gcaatcaaga cagtgcggtg ctggtgtaag gatagacata tatgacaaca gagttaagac 47640 tgagaatcca gaaagtctta catttatggt caactgttct ttcacaaggg tcccaggacc 47700 attcatgggg aaattaaaat agtcttttca acaactggtg cttgggcaga tggatatata 47760 gataccaatg cacttatgaa aaaaatggat gaaataggaa gcttcactac attctactgc 47820 atgctgggtc attttcaatc atttaggtgg caacactgac aagataacag aaaaatggag 47880 gcagtaacat gtgaaaggca aaatggttgt tgttttttaa aaaagggaca atatccatca 47940 tgaatttact tacactccag gcaaaggtta ttaaaagaaa aaaaaaattc cttaactgaa 48000 atgtggaagg ggtatcaaga gcagacccta caagaattcc agtgactcct cactgttcaa 48060 ctaagagatg taccccacca tgccgtgcta ccatggaagc attggaggca ctctgggggt 48120 tgatgacgtc ttcatggatg aggtacttta aaatgtggtc atgaagagta tttgagaaat 48180 atgacaagat gctgggtagg aatgcaggga gaaaagtgtg taacccacgg ccaaattgga 48240 aagatcagtg agggggcaat ttgtggaggc actgaacgca gagaatatta aaattagcaa 48300 gatggtgttc tagcacaatg aaaaggattg gaagagggag atcagagtca gggaattaaa 48360 ttaggcagct gctaagaatg tccaggtgag tcagaggatc aggacctgta agggcagtat 48420 aaataaagga ggaatgacag gagggggttt acggggaaag aattgacaac ctgtgacaat 48480 tgaggaatga gagattttga tgattggggt gaaggttaca tttcgtaaaa agaaacaaag 48540 aatggtcgac agagacgcaa gatgaagaat tttgttttta ggcctactga ctttgaggta 48600 gcgggaagaa atcctggaga cagaggtctg agtagaagat acagaattgg ggaagaatct 48660 ttgggagtgc ctgaggttga ccagagagaa ctgggcaaga acaggtaagg actttaagca 48720 gaactggagg agtatccatc caaaatctgg gtaaattggg aaggaaaaat aagcagccag 48780 agaagcaaca gctcaagtta gggtacagtc aaggttatag atacgtgtta ctgattttgg 48840 caatgaggag gttataagga tccttgaaga ctgtactttc agtgaaactg tcatggatta 48900 gtagcctttc acagtgatat ctaccccaca cctgcatcga aatcttgcag tggctgttaa 48960 caaatgccaa cccactaaca gggaggggaa aaaaagactt gggactctgt acttgtaaaa 49020 ccctctaccc tccccaggca attctttaca cactaacact gttgaggtaa aaggaggcaa 49080 ccaaatgagg gagcaaataa aatggaaggt gtgttttgga ttatacagtg gcccatggaa 49140 gtgtgggagg ggtacagatg gcccttagac agacactggt ggaaagtcag aaaaaaaaat 49200 tgcggtaagc aggtaaaggg atcaagagta cacaggaact ggtcttggga cgacatttct 49260 ttctctgaca gtttgtatgg aattcttggg gaaattcctc aaaggggcct ggaatctcag 49320 aagggtcatg tttttaatgg gaacagggag tgatgctgcc ccattacaac catctaacag 49380 aatgtctgta ccgaggaggg aggaataaca gcaaggtctg tttgaagcct cattttcaag 49440 tttctttttg atatggatct ccctatacaa gcaagcatcc ccaaaagtag ttatctcagg 49500 aaaccaaggt taggatgacc agctcatttg ctggagctgc caaggtccag aaaagtttgg 49560 ctgcaggctg ttttcatgtt ttatgtttga aatgttctac aatgaaagtt aaaaaaagtt 49620 agcatttatt tggaaaacca gttactttag tttatggttc ctttttttcc ctccagagct 49680 tcctggagat tgaggtctaa ttcaaagaaa accaaactat acaatagagt acctgggcaa 49740 aaaagtactt ttataacata acatttgggg tagaggaagt atccactatc gtcaaaactt 49800 ctatgttttc ctcttcctta ttgttcaggg acattccatg cagcaaaagt aaggggagtg 49860 acaacatgcc tagcataatt aagcaagcta gagcagctag tctgtgcaac tgatgatttt 49920 ttccctctaa aattttaagg gtaggttcat tgtgactctg ttagaagtct acttgatgtg 49980 aattctgtat ctgataacct atttcaatta tcactttaaa atttgtcata tggatacatt 50040 attacaatca tagaacttca gtaccgtaat aataaaactt gagaactgaa gagcacacat 50100 ttcttcacga atttattata taaaacgccc tcagagtatt taatttctcc tcactttaat 50160 tacacattaa gaagcacagt ggatgagaag cctttaagat gactacagtt gcacgaaggt 50220 ccctttcatc aaggtagcgt acgtacctta acagtgttct aaaggctggc ccagaaaaac 50280 cccatgttac cttatcacaa tatggaaagc attgtcttct ttttccacta aattatggtg 50340 aaaagtgcca cagttttatt tagcattatg gtacataaca gttctgtctc aattatgaaa 50400 aaattaaaat aatcctgaaa gacatccttt ttctcccccc aatgatttga aagctgcatt 50460 tttcctgcca atttcaaaca aatcatcagg ttgatctaca gtaatcagtt aaaacaatca 50520 ccaaggcaca agctcagcac attagctata gcttgtagca aaaggatata tcaatgtctc 50580 accttagtta aaaatacata atccttttat tttataatgc aataaaagaa attaacatca 50640 catacacaga agactaggaa aggggaaact acttacttcc gaaaatccag taatgtaaac 50700 ctacttgtac ttttccatag tacatgaaag taatgtttaa catgttttga attaaattta 50760 acctgtgggg ctatacaatg taattcttag gagtaatagt ttcattcatt tccaggtcag 50820 cttactgtat gattaagtaa cacaaggcac agtagccatc tttttcatta tgttgcaaca 50880 ctgatcacgt gcctcgataa aatggctgat tcaacaagat gatggcaaca cgaaggggag 50940 actttggatt gtctatttaa aatctaggta ataagtaatt aataaaaact ctatcttaag 51000 tgcactttca catgcttttt gtttataata aacaacaaac ttcctaactt tgttgcaata 51060 ggcttgacta ccatttcatt tggccaaatg cactttcccc agtaaactta aaataacaag 51120 aacaacaaga acaaaaatcc ctgtcctttc atatactaag aaagaggatt ggctactgaa 51180 acagttcatt gcaagacaca tgaagacaac atactgtggc atgagttgtt tttttaattt 51240 gttgtgctgt tactaaagtt ctgagggctg cagttaaaac attccaattt ctcccttcca 51300 tctttattga ttctcaagat tttgcacaga aaactctttg ggggctagaa cagcagtaat 51360 tgcatcacac tgtttcaaag acttcaagtt tcaaaagcaa atcattaaaa aaaaatacag 51420 ttcctgattt gagttagata cagggacaaa aaagtagcac atacttgaag gttacatggt 51480 ctacaaatgg tggcaatatt tttcttggga gagtagttct gttggtatat attttttaaa 51540 tactcaaaag gctcaacctc aagcagtaat aaacacaagc aaaagtgatt taacccttaa 51600 aataaatatt cagaaaaacc tctctgtaca tacaagtgaa agaatatgta acactttcac 51660 gcaaaaaaat aattataata ataataaagg atttgttcat atatgtagct gaaatctgct 51720 gttccagccc acatgtcccc aagaaagaag ggaggcacag acagaggtgt gactactgtg 51780 gttcactatc ttacagcctt tttgtactgg gacactatca ccaccaaaca tttatccctc 51840 ttgttatatt tttaaaattt tttaaatttt ttcttttttt tttcttcctt ttttttgttt 51900 tattttgttt tgttttacag catgccaaat cctttggcat acgtgatggc cttcaacaat 51960 ctctctttaa gtttttcttt gcttgaatat tccggaagta aaagcacatt aaagcaagta 52020 tgagatgtag gtaacctaaa tagagaaaag gggaaaaaac aggaaaataa taagtcatgg 52080 gaaatacact tagaattata tatagttgag atggtttgca atgccaacta tacattaatg 52140 caaatcataa actttttgtt gtgtaactac caagaatcag tttgtcttta tcctataaat 52200 tactcaaagc tagtaacaat gatgataaga tacttatcca ttgagttttt actacatacc 52260 agataccgtt ttaggtattt aattattaca gttcatttca ctaaatcttt ttccacaaca 52320 aaaccacaga gaggacatca ataaatgcac ttcagaggtt aggtcactga gaagtaactt 52380 cctctaaggt ggagaaaata ttcaaacctg gtttacaaca tttcaaactg tgtgctctta 52440 aatgcttatt agaaatactg ctggcaatat gactatgaaa atgataacag gattctagaa 52500 taatcgaatg ataatcttcc aagcctcaat gtaaccattc taaatagatt atcatgtaac 52560 atggctttca actaacaagc tgggaatcaa aaaagtaaat gaatcatact aatttgaaaa 52620 attccaaacc aatgtgagtc ccataataat ttttaactag ggcaattcct taaaagtttc 52680 ctcacacaat gacagcaaaa tattttctca attgtctaat atgatttgag gatttgtaca 52740 taaaatcaca aaggtgctta gaaactataa agacagttca tatgtgtgtg atgaggaatg 52800 caaggttttc agtaggtata gagtcaccac ttaatcatta cctttctgtg tctgggccat 52860 ttttggctat aatcatcttt aattttccta gtcctcccac aggtgctctg tctgtgcccg 52920 ttgtaaactg caagaagagt cttttctgtt catctgtaaa tgaatgaacg atttcccaga 52980 actccctaat gagaaaaaat acaatactgg tttcagtttg gcattcatta tgactggtac 53040 taatataagc ttatgatttg catttaaact atattaagag acaacttgga agttaattat 53100 caggataata tcacttctgg tgatttaata atttccaagc aaatttatct taaacagttc 53160 tgaatacata aaaatttaga ttacaatata gtaaaatatt agtactacaa tagtaaaaaa 53220 ttgagaaaac ccaagtgtgt aataacagga aatgactatg taaactatgg tataatcaca 53280 ttatgtagag tcagtaacaa acaaaagaca aaatcctatg aattgaaaaa gactgaaagg 53340 aatattggga aagattaact ccaggtgcct ttgggtatat attttattta tcctttctcc 53400 attattctcc ttgtctactc atcctttaac tcagctttgg gggggaaaag tgatacagat 53460 taaggacaaa agaaaaaaaa agaccccctg ccccaaccaa ctggccccaa atgcaaacaa 53520 ctatatacat acctaatagc agtaatacaa aagttcaatt tttataggaa ctagaatact 53580 tttaacaagt aatatgtgct gtgtatggag gaggagaatt attctgacat ttctgccacg 53640 tgcagttatt ttaagagaat gatttatcct ctggcattcc taaaatctat gtaataaaag 53700 ctatgtttta tgacacttac gttagtttga gttctaaaaa acgaaataca agctcataaa 53760 gtgcaatctt gaagtttgtt tgaataatca ggcatctata aaacatatat acactagttc 53820 atagttaaat aatttttttt tttttttttt tttttttttt aagacagagt ctcactctgt 53880 cacccaggct ggagtgcagt ggtgcgatct cagctcatgc aagctccgcc tcctgggttc 53940 agaccattct cctacctcag cctcccaagt agctgggact acaggtgccc gccaccacac 54000 ctggctaatt tttttgtact tttagtagag gtgtggtttc accgtgttag ccaggatggt 54060 ctctatctcc tgacctcatg atctgcccac cttggcctcc caaagtgctg ggattgctgg 54120 catgagccac cacgcctggt ctatagctaa ataatgttaa gattaaaaca ttttttttaa 54180 aaagtatttt tagtcgctta tataaaatgc attttaatat ttattcagaa agttctttcc 54240 agagcctggt gtggtggctc acgcctgtaa tccgagcact ttggaaggct aaggtgggtg 54300 gatcacctga ggtcaggggt tcgagatcag cctgaccaac atgttgaaac cctatctcta 54360 ctaaaataca aaaattagcc gggtgtggtg gcggatgcct gtaacctcag ctacttggga 54420 ggccgaggca ggagaatcgc ttgaacacag gaggtggagg ctacaatgag ctgagatcac 54480 accattgcac tctagcctgg gaaacaagag caccactcca tctcaacaaa caaacaaaca 54540 aaattatttc cagaatgtta gcagagaaca ccacacatcc caaatcagta attacaattt 54600 tctagttttt gatattctaa tattccaaca tactattttt attaccaaaa tgctggcatt 54660 tttgttgctg caacaccatt tatctgaaat aaattaaagg ttttattaga attcttggct 54720 ttctccaatc tcttgccact tcccttccct gcccctctac gaatctacca gtcagccaga 54780 gaaaacaaaa aagaaacaca caaccacaga aaacgggacg tgaaactagc aggagcatct 54840 ctcagttaag gaggaaagga atcagacccc ggttcatgac attccttttg gggaggctgg 54900 caagagaaaa taagtctgct gtagcacaca gccctccaac atagcagaaa agctgccctg 54960 cagtgggtgg taataaagcc tcctcaaact gcagtggggc tctgaagctt aactgaacca 55020 gctacaccta aggaggcaga tcaaagagca ccaccgaaga ggagagacag accctgcagg 55080 aagtggcaga tgagtagtgg tcacaatgac cagtcccgct atatagctgc tgctttggtc 55140 tttcttttaa atgaaacctt taaaaatttt atacaatgaa aataattagg gaacaaaatt 55200 tgtctcttcc tataagtgtt atgtgtgtta cattaacacg ttgaattaaa taagaatgca 55260 tttatttaga aagctgaaga aaaaatgaag aggcttccag gtttccacaa aaaagtggtg 55320 gctgtatcga tcacatccta ctaacatctc taaaaatcta tccagatcaa aaaggggaga 55380 aataaaaaaa aaaaccccta tgacttaagt ctagagtaaa actaggagac agagcaataa 55440 actccaaata ccatagaagt ggggaaatga gcagggtcca gcaggagcta cattgaagag 55500 tggcttgtgc agaatcatac tgattaggga tcacctaagg ccagacggca cccgcctcca 55560 ccacccaccc ctcaacagag cactactgag ggcaggttag agcactggca acggggtggt 55620 taaaggaagg actacagaaa agtagttggg tccagcaatg gcaggctcag gaatgcacca 55680 tgcatgaaag gaagacgggt accttggaaa gcagaagtgt cccttaagtg gctgtaaaga 55740 ggtggaagca gctaatgaaa aagaatcttc attaagtgga tggagctgaa aaatcagcaa 55800 gtggtgattc tgcccttact aaagcaacag aagagggacg ccttcagcca ggacccctaa 55860 aagccataca aattcctctc tgctccactc taaggtctag taataacatg tccagaaaaa 55920 aagtaacatc tattatagaa acataaacaa gaaaaacaga attcctaagt ccaaataaag 55980 ttattatgga aagagtctgg caaatgagaa gcaaaacttt ccggtagaca aaagtacacc 56040 agaaaaattc agtcataaac aacaggaaac tcgtaacacc acattccaac acaaagggag 56100 aatgtagcag cagacaagac agaccaccaa tgatgagaaa tacaaattca gagagaaatg 56160 agcacatctt aaatagaaat aagaatacta aaaaatactg aagaaatatg caaagtaatt 56220 ttggaaataa aggctaattt tattataagg tgaccaaaga agaagcaata tgactaaaat 56280 ttctactgag gacagagtct agaaaattaa aaaacaaaga aaatgaataa aataaaccta 56340 actaaagaaa tgcgtatcaa agcatagtaa cgaaaaagat taatagctga ctacataaac 56400 ataaaagctt tcacctggca aaaatgctat aagcaaggtt aaaagacaaa tggcaaactg 56460 ggaaaaaata tttgcaaatt taccagcgtt aaaggactaa tctccttaac atataaagtt 56520 tctaaaaatg aagaaaacaa ccgagcagca aaatgagcaa aagaccatat aaaactataa 56580 acagctctta agtacaagaa aaaatgtcca tcatcattca taactaaggt aaactcaaaa 56640 attgtaagta tagtaaaata ccatttctca attggcagat aagtaaacat ccacatttaa 56700 caacacatta tgtttggaaa gttttaagaa aagagagact gttgtaaact ggtgggaatg 56760 caaaatgtta cttttctgtg aaggagaatt tggcagtatc tagcaaaatt atatatgcat 56820 ctaccatttg atgcaacaat cccacttcta acaatttatc ttaatgatac cttacatatg 56880 taaggaataa tgcatgaaca taagaggatt cactgtgaca ttagtactaa cagcaaaagg 56940 ttaaaaataa cctcgatgcc tataaatatt gataagctat gccgcatcca cacaaagtag 57000 cagtattcag tcctacaaaa caaaatggaa aacacctctg caatgatgta ggatgattct 57060 caggatacac tagaaagatt actttcctag ttctgtcctc tgataaggcc tacaagtagt 57120 aacattcaaa accaaaggcc atactttgca tctaaaatct gacttctaaa tgccattctc 57180 caacaattta ttggaaaaat aacttattcc aggactgaga ctgaatgttc gagattagct 57240 agaaatttca aaatctaata gagtcatttt aaaagcacaa gaaggctaag gaatttgaat 57300 atcatttaga gtaatgactg tgaaacatat taaatacaaa aacactgagt tcttaatatt 57360 caaaaaggca gcaaaaccaa ccaaaaaaca aaattaaatt gtcactatta aagttattac 57420 attaacttct tactctaaaa accttaaatc tattttatca tgccttttca gtagaactgt 57480 ttttcaaggt aatcgaatgg catccaatga tgagaaaaaa cagtgccagg tatatatgta 57540 ggacaagcag atggaatttt tttttcccta aacagccatt ttgcaatccc aatgagataa 57600 cagattaatg atactgataa atacggaaat caggtgaagg gcagatggca cgttctggaa 57660 agatgatgat agcagtgaca tagttattat ttatttattt atttttttgg ttttattccc 57720 tcccaacctc ccctacaaaa agagcaaact gagaaaacca aagacccaga gacattatct 57780 ataacaaaac catgaaccat tgcatataag tggacaaaac aaagctctga caagtacaag 57840 actggttagt aaggaagcag atggaaggta actgactggg tttcttacag ccctgtgaac 57900 aggaaaaacc tcaatactgc caacccactg gaaagcacag gccatctgaa aacagggcta 57960 aaagtttaaa aaagttctac aggatctaat ttgcagatga ttacaaaggg atcatgatgc 58020 agtaagctct gggcccttaa aattcccgaa taccaaatcc tcccaccaaa acaaaccatg 58080 taccaaggaa aaacttgtgg gaataacttc caaatggacc aaatcaaaga taataaagac 58140 caaaaaaagt tcaaatagtg tgtgtggggt agaggagtaa aggcggcagt ttcagaaagc 58200 acaagggcat atttttgacc attttacaaa aacacagact tctccctgtc cctaaaaagc 58260 aagaaaagtt atcctggcct atctctccct tgtgcaagta tgagacactc atttccctca 58320 caaaaaaaga aaaataaata cataaccaac agaacagagt gcaacagtat aattattaga 58380 gaaagagtat gtgcatatac atgagaatgg tgtccctaca gaaaatgaaa gtaaaccaaa 58440 aaatatggaa ataaaacatg aaaactgtaa acaaatttca aactgagcta aaaagaattt 58500 taaaaataac agatccttag aaatgggaaa tttcagaatg agggtaactg aagaaaagaa 58560 agccatgaca caactaagga gtaattagaa atgcaaggaa aaatatcaca tcaaacacac 58620 aaaaaaaact aaaactaaat tagaagaaac ataaaggtga ataaaacaat actactacta 58680 gaaactgaag gcagaggaaa aatcttaaaa tcaaaaacaa gtaaagccat gcctgagact 58740 ctcctagatg gtccagagac acagtgatgc tgtgcactgg caggaggaat tctgctgtaa 58800 ctggtcctgg gagtgttcac ctttcctgta agtgttccac agcccaggga cacaatgtgg 58860 tcaggagcac tgccaggaac accagcaagg gggagcctgc cacaataggc acaaggctca 58920 cgaagcactc tctggcctac gaaaatctag tgggggtgct cttccctcac ccaaacacac 58980 tctgtgcagc tcagcctgga gaagccccct caagcagcac tactggaacc cgtgcgagcc 59040 ccagtggact gagataaaag caacaaacca aaatagcacc acaaaggctc tgaaaaatgg 59100 tcactggaac cacagcccac aaatatatgc tagcacctac atgctaaacc taaacaggtt 59160 actactgaag ttaaaatttt ttaaaagtac agagtctcct gtataataac taaaatgtcc 59220 gagacacaat ccaaaactta tctgtcatac caagaaccag gaaaatcaca tgaaggaaag 59280 aaaatcaacg ccaacactgg gatgagtaag atgttgaaat tatctgacaa ggatcttaat 59340 gctgccatca cagaaatgat ttgacaagca attacaagtt ctactgtttc aaaaatgaaa 59400 caatagaaaa tctcagcaaa gaaacagaag ttacaaggaa aaaaaaagca atggaaatta 59460 tagacctaaa aaatacaata ggagaaaaat aatcattaga tgggctcaac agtagagtga 59520 agatgacaaa ggacagaaat ctgaacaaaa gagagaaaat agactgaaaa atgaaccata 59580 cctcaggtac atgcggaaca ataacaaatg actcaacatt tgtatcatta gaggcctaga 59640 atggagacaa gagtgacgct gaaagaacac ctgaagaaat aatggttgaa aattttccat 59700 gtttggcgaa agacacaaac ttacagcttc aagaagctga gcgaacccca aacaacataa 59760 ataaaactat tcttcaggaa taaagggaaa ataaagtcat cttcagaaag agaaaaaaag 59820 aatttctcac tagcagaact gcttttgaag actggctaat ggaagtaata aaagatggaa 59880 tcttggaaaa ataatggaaa taacagaaac atgggtacat acaacagagc atcactccct 59940 tcataagttc tataagtcat attggataac tgatacaaaa actgttaaca ggattaatcc 60000 tcaaaacaat actatttaaa agtggggaaa gagacgtaac tgaaattaag gtttctacat 60060 ctcattccaa gtgatggtat tgatggcagt gaatggtgat aagtcacatt atctataatg 60120 tgatgcccac aatgaccatg aaaacaacta taaaaaacac ataaaaggcc aggcacggtg 60180 gctcatgcct gtaattccag cactttggga ggctgaggcg gacagatcac aagttcaaga 60240 gttcgagacc agcctggcca atatggtgaa ccctcatctc taataaaaat acaaaaatta 60300 gccaggtatg gtggcatgtg cctgtagtcc cagctaccca ggaggctgag gcaggaagat 60360 tgcttgaacc tgggaggccg atgttgtagt gagccaagat tgtgcgactg cactccactg 60420 cactgcagcc tgggcaacag agcaagactc catctcaaaa caaaacaaaa caaacccaaa 60480 caccaaataa atcaagggaa aatcttaaaa aatattcaag taatcgtgga acacaataaa 60540 taaataaata accataaaca gaagacagaa acagaaaaca ataaaatggc agacttcgcc 60600 ctaacatatc aataattacc ttaaatagaa atggtctaaa taaacaaaag gtagagacta 60660 acagttttta ttaaaatgac aactatatgc tgtttacaag agattcattt caaattcagc 60720 aacacaggat gaaagtaaaa tgatagtaaa agacagatca tgcaaacatt taaacagaaa 60780 tggttacatt cctatcagat tcagagcaaa gaaaactgca aaacagaaaa atcttaaatg 60840 ataaaggatc aatcaccaag acatagtaat tctaagtggg tatgaaccaa atgacagagc 60900 ctcaaaataa atgaaacaaa accctatgac agagataaag agataaatct cagaagcaga 60960 cctatataca tattctcaac tgatttttaa catatgtgaa aaaaacaatt caatgaagga 61020 agaacatacc tagaaaatac acaaaaaaac cccaaatgga ctcttggtat ttaatcccag 61080 agaaacacaa actttttgtt tataactaac atcacagtta atggtaaata ttatagtctc 61140 tctcaataaa atgaggaata aagtaagaat accttctacc gaaggttcta gccaatgcaa 61200 cagaggaaca gtaataaatc acataaagat tggaaagaaa gaaacctgtc ttgatttgta 61260 gatgacatag ctggttacca gaaaacccta tgaaatctac taaataacta ctagaataca 61320 tcaatttaga aaggttatag gatacaaggt caatatataa aaatcaattt tatttcaata 61380 tttcaatata gtagtaaaaa acaagtgaaa agcagtattt aaaaatacca ctaatagcat 61440 tagaaacata ttttaaatgt attcctaacc aaagagtaaa tgatttcaac attaaaaact 61500 ttataaaact gctgagataa actaacaaac atttaaataa atggagagag gtacggtgtt 61560 caaggattgg aagaatatat tgttaaaatg tgaattctct ccaaattgac ctaccccgat 61620 caaagcaacc caaatcaaaa tctctgcagg ctttgccctt tttttcattt gtaaaaatta 61680 actgattcta atatttatat gcaaataaaa gagtcaaagc aacctaatga aaaagttgtg 61740 ggactcacag catctgattt gaagctgcag taactataac agtgtcgttt tggcaaaagg 61800 accaaacaaa ttaatagaac agaatggaga ttccagaaac aaggctcaca cacagattga 61860 ttttcaacaa aggtgcaaaa gcaattcaat ggggaaagag aagtctcttt aacacatggt 61920 actggaacaa ataaataaaa ctatttagaa aatgaatgac atccactatc taacagcatc 61980 acaaaaattt actggtggtg gatcacagat ttacacataa aatttaaacc tatattatag 62040 tattagaaga aaaaataaga tatttgtgcc tttgggctag gcaaagatat aaaaggacaa 62100 aaaaaataaa agaaaaaatc aattagactt caaaaattaa taatttctgc tcaccagaat 62160 acacttaaga aaatgaagcc acagacttgg agaaaataat cataaactac atatcagaaa 62220 tgggcctttt atatagaata tacggtattc cccacttacc catggggaat gctttccaag 62280 acctccagta gatgtctgaa attgcaaaaa ccctgtatat accattcatg atttattttt 62340 ccttcttcac aattccataa atactcattt ttaccacaga ttttagcaac ctcaacatat 62400 gatttttaaa ttctttcctt aaaggaagca ctttccccag cttctctttg gcatattcga 62460 atttccaaca tcactgctct tgtgcttcag ggccattatt aagtaaaatg agggttactt 62520 gaacacaagc atgcgatact gcaacagtcg atctgaccaa tagactcaaa gtggtgggta 62580 gtctagacaa catggatata ctggaaaaag gataattcat gccctgggtg gaaaggtggg 62640 agatttcacc atgttactca gaatagcatg tattttaaaa cttaagagtt gttggctggg 62700 cgcagtggct cacacctgta atcccagcac tttggaaggc tgaggtggaa ggattgctag 62760 agtccagggg tttgaaacca gcctgggcaa cacagtgaga ccctgtttct acaaaaacaa 62820 acaaaacaaa acaaaacaaa aaaactaaaa attagctgca caactgtggt accagctact 62880 cagaagactg aggtaagaag actgcatgag cccacgagtt tcagtttata ataacctgta 62940 gtcatgctac tgcactccag cctggatgat aaagactttg tctcttaaaa aaaaaaaacc 63000 aaccaaccaa ccaaccaacc aaccaaccaa ccaaccctcc ctccccaacc cacacccacc 63060 aacacacaca cacatcaaaa actcttgagt tattcatggc attttctact taatattttt 63120 ggaccactgc tgatcaaaga taactgaaac caaaaaaaaa gcaaactaaa gataaggcat 63180 aatgctatat tttaagaaaa tatctatagt caatagaaat acaaaaatcc aatattaaaa 63240 atgaggaaaa gacactttta gttaaatatg tacctactat atgctttgga aactccactc 63300 ctacgtgttt gcccaggaga aataaaacat ttccacaata agactagaca gctttattca 63360 caatagttcc aaactggaaa caatccaact gtctaccaac aggtaaaaaa acacattttg 63420 catattcata taatgcaaca gtactccata atttttttaa aggcactata aatcaatgca 63480 ataacatgga tgaatctaaa gagtctcgat gcagtacaag tatataagat tccattcata 63540 agaaattcta gagcagacaa aagtaatgta cagtgacagc aattaggaca gttattgtct 63600 gttctaatgg gggacagaga ttcactggaa gggaaaacat gggaactctg tgttaatgga 63660 catagtctat accttgactg aaatatggtt acataaacgt aatttttaaa aacaaaccca 63720 gttaagccct gggtatttca ctgtattaaa attttacccc acacaacatc gacaccacca 63780 ttattaccac cacattgatt aacatttaga gagcagttag ggaatcacat tattttgaaa 63840 attagtaaat aatgggaaag aattaagcat tattgtatct gataagtaca tatttatata 63900 catgtataca ggtcctatat gtggatctgt aatttagggt agtcatagag ttgatgagaa 63960 agagtttttc ttaagaagta ttacaggtaa taaaggaacg aggaataaag aattcaaata 64020 tcacaatttt gcaaccctta atgaattagc agatctaggc aatcagaatc tatgataaaa 64080 attactagaa aagacagaaa gcaagtgaga ctttaagtta ttcctgtaaa ccaacatcta 64140 tgaagtattt gggaaggaaa taaagtctga atctgttttt cgtttttttt gagacagagt 64200 ctcactttgt tgcccaggct ggagtgcagt ggtgtgatct aggctcactg caacctccgc 64260 ctcctaggtt caagagactc tcctgcctca gcctcccgag gagctgggat tacaggtggc 64320 tgccaccaca cccagctaat ttttgtatat ttagtagaga cggagtttca ccatgttggc 64380 caggctnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn 64440 nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn 64500 nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn 64560 nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn tgctaggcac ggtggctcac 64620 gcctgtaatc ccagcactgt aggaggccaa ggcgggcgga tcacctgagg tcaggagttt 64680 gagaccagcc tggccaacat ggcaaaaccg tatctctact aaaaatacaa acattagcca 64740 ggcgtagtgg tgtgcatctg taaccctagc tactcaggag actgaggcag gagaatcacc 64800 tgaacccggg aagcggaggt tgcaatgagc tgagaccacg ccaaactgta ctccagcctg 64860 aatgacagag caagactgtt tcaaaaaaaa aaaaaaaaat taacaaaatc ttatttctag 64920 tggtttacta ttaattatgc tggcaatttt tagctgaaat atattaagca gccttgctgt 64980 tatttttatg aattctgcaa caataatacc aaccaaaata tctatacagg catatcccag 65040 agatactgcc agttcagttt tagactatgg caaataaagt gattatggca gtaaagtgag 65100 tcacacacat ttttttgttt cccagtgctt acagaagtta tgtttacact atactgtagt 65160 caagtgtgta atagcattgc ctaaaaataa gtacattatc ttaatttaaa atcattgcta 65220 aaaatgctaa tgaagtgagc acattttctt ggaaaaatgg tgctggcaga cctgcttgat 65280 gcagggttgc caccaaaatc acaaagtatc tgcaaagtgc aataaagtga gatatacctg 65340 tattgtcctt tttctcctgt tattacaagc actattttaa gtcttcaact acagaatact 65400 tgtagactat ttaatgaatt aatattttca tcatatttat attgagaaaa ttaagctgaa 65460 tttagttaga aaaggtttag aatatcatca actctgatga tgagttggaa gctactttat 65520 ctgtcatttt tcacataaca ctagcttgcc cttcaaatca tatatttaaa aatgacctta 65580 agatacacac caagtaggga ttatgttgtt ataaaaagct agaaataaaa ttaagacttt 65640 aatttcaaag ataatttctc tataaagaat agcacaagat atgttcaact attctcagag 65700 atgcatcaag atatgacttc ataactatta gaaattatat ctatgatcaa tcatattaca 65760 gagatattgc tgttatactc cttgtgccct ttaatgaatc acctttgaaa ctgaataggt 65820 agcagcatag aggttgctaa gagtaaatac atttaccact gctgccagaa atgaccaaag 65880 gtgcaccaaa aagaagaaat actggtgaat tcccacaaac tacaatgaag aaccttataa 65940 aataacagaa caaatgaata taacgtaaca tacagccatc tcttggtata cgtgacaggg 66000 attggttccc ggactgcttg tgtataccaa aatccatgca cactcaagtt ccgcagttgg 66060 ccctgcggac ctggtgtgta tgaaagtcag ccctctgtat atgcagcttc tgagtcccac 66120 caatactgga tcggccctta gttgagaaaa aaaatctgca tgttagagga cccatgaagt 66180 tcacagctgc attgttcaag ggtcaactgt aatataaaaa taacatttac tgctagagtt 66240 ggtactcatt ctagtgttta tatacttgag tcttagagca atagccttgg gagacaactt 66300 ccaggaaggt acctgtttgc ataccttctc actgcaatcc atcagtggct gccaaaaggg 66360 tatttttgtc tcttgaacca gtctcagtac gggatgggga agcctatgtc cttcagaatt 66420 ggatggcata gtacacagaa gtagacagta cagtagcaag ggcatttgct taaaagcaga 66480 tagaattggg agcctctaca tctttctgtg agaattcagg gctcagtttc ttaaggtgta 66540 aaatggaaat actactatgt atctggacat attatcttaa gaattaaata aaacactgta 66600 ccatttcact caaaaggtgc ttgatcctgg gtagccatgt agttcacaaa tgcagagttc 66660 aacagaaagg aaaaatatgc agaagtggta gccttatttg aattatcttc taaccagcag 66720 taagcatact cttagccagt gagaaatact agataatcca taccccaaat gcaggagaac 66780 acatgagact tacatataac aacacttcat tcatgaaagc aatcacaaga ttagctctga 66840 aaaacggtga ttatattaca aacacaaatc taagtatata gataacaatt tgtgagtttg 66900 cttatttggg aattagtgcc tagagataaa ggtcagaagc aaaatcacac acccctttgg 66960 tgaatcaaat cttcctttga agaattaagt acctcaccta atcagaacag agtccctggt 67020 atagccaccg tcatattctg tagtttcttc taatgcttgg aaatctagat tctgcaaatt 67080 taagaaaata tgtcttagta tctgctatac tactgtatca ttacaaacaa taaattgata 67140 catgactttc tgcagacacc tgctttctta cccggcttcc acatataagc aattcaattt 67200 cttctggtct gaataagtac tttaagggag attcattggt caccatatga aaacctctcc 67260 gaaaagcctt gaactgtttt tctactgatt tattgagaat gtagtcagaa taaagattga 67320 caaattcctg tagaaaacat taatcacaag aacttcttat aatatgctat gcaaacaaaa 67380 cacaagttat tgggctgcat agctttttaa tttttccaag aaaaaaacat tcaagaatat 67440 tcttaaaaat tcaattttac acctacaaag aaaactactt cttacaattt cacaattctc 67500 tgttatggcc aatattaaac tatgaaaagg ccatatacat acaactgtca tacatataaa 67560 tgtcaatttt gacaatgtat taaacagaac tgaatataaa tgctggagac acagaaaatt 67620 ctttaggttc gctcaactag gtatgcagac agacacattt aaatcatgta cccatctatt 67680 tataaatgcc accgttttaa gagagtataa tgtatttgat ttaatcaaac caggaagtcc 67740 catgttttct accatagagt atttggtaag ctgcctacgg tatccagttc agcaaaaatg 67800 tggaactact gactggcaca taaactactg tatcaaatca taaaaggaaa atgtgctttg 67860 tacccttagt gtgtataata cttaataaaa aaattatacc aatataaata tgtttctcaa 67920 aggtgtacta tatgttcgtc ataatgtttt ccttgtcatg ttctgggtta ttcccattcc 67980 agacgaacac attttagtca acagaagccc aaatctaatg taaagaatac ttttcagaaa 68040 agtatttaca tcacacacag gatatgcatg tgtaaattaa atgtaatttt tatttgttct 68100 gtgataaaga ccttaatcat gaggttcctg tttacagctt aatacaggaa acaccctgct 68160 tcttgcttta tcctacaacc acacttagct attgactgtc tcctgtttca tgtcctcttt 68220 ctctaaaagg ggctttagtg cccaactgtg tgctttcata ccagcttata ttcaagattt 68280 agaaaactgg actctagcat ttacataaac ttggttactt gatttgtgtg tttttttttg 68340 tacagactgt attagatact tctttaaaaa ttataagcat acatgctttg aaattattag 68400 agacaaaaca tgacataaaa acatttatta ccttcctgtt ttcatttgta attggaattt 68460 tatcaccatt ttcctttaga tcatacatca ttgggttacc aaaaagatct gtctgtgata 68520 tctggaaagt gatcatcatg tcgtcttcca cattcccttc atactccaat aaatctttta 68580 aactctgata cagaacctag caaccagaaa tggtaaattg aggccaccat agaactacaa 68640 aatacaacaa ataatttata tcactcttct tagaagataa caaaaatctt atcaataaaa 68700 attgtaaaaa gtgtagaaag tatccttcca gtcccccaaa tagtttccaa cctataaaag 68760 aaagactgtc agtcactgtg atgttccatt ctctgctgag aaactccaca ccaccaattt 68820 agcaacagat ttcacactgt gctctataag aaattctgtg gtgtctcaag gtgagggtgg 68880 gggtggcagc aggcacactc actgtagcta ccaagaccct tagccagggc tgctctgatt 68940 ttacctatct cttaagattt cactaaagca caaacaaaat gtttagaaac acttctctat 69000 ggaatcaatc tttaaaaagc tttgtgctga cagcaatata taaaaatgtc cccctttgag 69060 tttttaagtg tttgtcgtac ttcggtcaga ttaaaacatt atattattga taaaagtatc 69120 aacaaagatt ctaaacaaaa actttaaaat tttgatataa ataaattgta tttttgcatt 69180 taaataaaat ctaagagact gaattaaaaa atgacaactt actgggtgag agtctcccaa 69240 gtcacgaaaa gttccttttt tccccattag ctttctgtag acaaccatgg gaaaatgtac 69300 atccagtata cagttattgt aaatagccag acccagtact atgccaatca gagtaaactg 69360 accctcagtt tcaaaagaag acggattaaa ccaaaacaat tttgtagatt catcgtatgt 69420 gaacatacct gtaagaaatg attttttaaa atacattact tttgtatttt attaaggaat 69480 gataacacaa atgtaaattt aaaataatta tgcatataaa acatttaaaa tatatgtaat 69540 taggcatgca acattgattt ttattatatt agcacttgag aaaacaatgt ccacatatat 69600 ctaactgtta taaattgggg tgaatagtga tatgtaattt tatgaagcca aaggaataaa 69660 gtagtaagta atttggtggc atcgggtaga aaaatacgtt cattaaattc aagctttcta 69720 attttctatt gtaacataag aaaagttata ttcatacttt atccacccat agctgaaaaa 69780 taaacataaa aaaaccaaaa aatggctata ttttgaaagt gtttcattta taaaaatata 69840 attacttata tttgtactac acgtactatt tttgaaaaca attttttatt ttttttcttg 69900 agatggaatc ttgctgtgtc gcccaggctg gactggagtg gcacgatttc agcttactgc 69960 aacctccgcc tcctaggttc aagagattct cctgcctcag cctcctgagt agctgagact 70020 ataggcgtgc atcaccatgc ccagctaatt ttttattttt agtagagaag gggtttcacc 70080 atgtttgcca ggatggtctc catctcttga cctcgtgatc tgcccgcctc agcctcccaa 70140 agtgctggga ttacaggcgt gagccaccac gcctggccta aaaaacaatt tttaatcaca 70200 gtaaggaaag gtttgttttt tcaaaatcag acaatggtgc catgaaattt ttctagcatt 70260 ttcctaataa aatcaaatga tctaaaatac ataaacttgg ataaatctga tgaacttaga 70320 taaacaaagc tatttaatac acattaatta tgggctaata tgtaaaaaga atagtagttt 70380 agtagtcttt caatttcaca tggtcttcac tatgcaatcc tcaatcacgg aggctttttt 70440 tttttttttt tttttttttt tgagacagag tctcactctg tcacccaggt tggagtgcag 70500 tggtgcgaac tcggcttact gcagctccac ctcccgggtt catgccattc tccggcctca 70560 gcctccggaa tagttgggac tacaggcgtc tgcgtagagg tcttttttat atcactcatt 70620 ggaaaattgg ggccgggtgt ggtagttcac acctgtaatc ccagcacttt ggggatactg 70680 aggcaggcag atcacttgag ctcaggagtt caagaccagc ctgggcaaga tggcgaaacc 70740 ccatctctac aaaaacacaa aaataagctg ggtgtggtag catgcgcccg tagtctcagc 70800 tacttgagag gttgatgcat gaggatggtt tgagtcttca gcctgggagg tggaggttgc 70860 agtgagccaa gatagagcca ctacactcca gcctgggcat cagagccaga tcctgcctcc 70920 ctccaccaaa aaataagact taaaaaaagg aaaattggaa tctttggttt tatctgaatg 70980 agtactacta aaaattgatt tcttcccttt taaatgacta gggaaaagaa attttaattg 71040 aatttagaat tttttcgttt tactaaatgt ttagtttcta ctgtgaaaca atgaaaacat 71100 cttaagaatt aagtctgaaa aaaaatctgt aatttccaat agaaaagtgg agcttagaaa 71160 tcagaaatca aattatatag tatataagta ttttaacgag agtttttaag aattttaaaa 71220 tctttgaaaa tgttattatc actttaagta taaaaatatg gagctttaac atgtttcctc 71280 gatcactaga tgcatgaatt aagcctaggc cattttctga atgcaaaatg gtttgaaaat 71340 taaacaactc atatttgagt ttcatggttt ctatctaaac attttttaca ggccaagtta 71400 caatatccat ggaaatgctt tcagttataa atatggtatt aacaggatca agaacagctg 71460 acaagtaatt acaattaata aatttgttca agttggcaat ggtgtgtcta aaaaattaat 71520 gaatttgata aaatgtcaca aatgcccttc cttggaacca agagttataa gctataagtt 71580 aatcagaata taactctgaa gttccatttt aggcacattt tctcatgttc cagggagaaa 71640 agcaccataa cctcctgtaa aatattcctt tttgatactt ctactgccat cacttcagtt 71700 accttactgg aactgcttaa tctatgtttt ttcttacaag tatttctgca tataatgcag 71760 tatgctttat agctaaggtt taacatttct agatacatca aaagctagag ctaaggttta 71820 ccaaatttaa gaaccttatg aagtttataa ttttgtatct caaaaaaagg gcacggtctt 71880 atgtatctgt gatttactta gaacaaacta catacaaatg gcatagtttt ttagttatta 71940 ataaaacact agctagacta tagataaagg gggtgtgtgt gtgtgactaa gaacagtaat 72000 agaaaggtca actcaattag aatcaacagg ctataacagc tcaaatctca aagctgaagg 72060 gaaatgacat acattattct acgcatactc ctcacaattc tgatggtacc ttcagtggaa 72120 accttttcct ataattgtca tgtactcaat tttaaatgta agaaagttca gttactaagt 72180 ggttgtattt acagtagaaa ctaaaccagt agagaattat gcagttaagt agactaccca 72240 aaagactgca tcttttccct gttctacttt atcacaaaag ggcaaaaact aaaattctga 72300 tctttcactt tcaaatgtcc atatcccatc agcctttccc aaactgtgtt caacaacaac 72360 tcttctggta gggcagaaaa agagttctgg agttcaaaaa gtttggggga aacattacct 72420 atattaagcc ccaataaatc ccatagcaaa taaaccttca tgtgatatca gctagtgttt 72480 cttaactttg agcatgacat acttgtgaga cagtctctca acactcttca aatcattgtt 72540 ctttgaagtt cacaggtcag gaaaaccgtg agtttgatga tggttttaga catcaaaaag 72600 caaagaaatc cctccaactg ttccaacgta ccattctaaa gtgctttcga ttcaatttac 72660 caaagagata atttccttca ttagaatatt ccttctaaga aatagaataa tttgaataaa 72720 ttagtgatac aaatcagtcc ctaaaaccta caaattcagt catgatgtgt gattccgggt 72780 aatccatacc aaatccttct tttgctgctc ttcatagctg agaatattta tcaactaaga 72840 taaacaaata actaactcaa aaagacaata tgacaccata atcacattac taaactattt 72900 accaatatct ggattgaaga tttcctccac aaccagctga aaaaattctt tggaaacacc 72960 tccttcatca actccttgtt ctccttcaaa ttccacatac aactgcttct tcaagtctgc 73020 aggattttcc atagcgatca tctctagcta gtgattgaaa agacaaacat gaaaagaaga 73080 tgactgctag tatcaagaca aaggcaaaat aaaaacaagg agtagggtta ggaaacaaat 73140 acaaattttt gactttttgt atgtaaatgg aaacagaaaa caaactgata aaaagccaat 73200 gaagacaaag attcagtctt aatgataatg aaaaagacac aaaagatacc ggcatagtaa 73260 aaagcttacg aactttactg atttattaca aaattaacat acagttaatt aagattttat 73320 tacttgtgtg ttaacaagtc tggactacac agttaggaca tggaaaagca gctaaatact 73380 ttcagcaaaa acaatggagt agaagtctga cctcaaaatt gtccattagt agtcctttat 73440 ttttattaga atagaaactc aagagttaag tcttaatatc tactgtcata agtaaaatat 73500 ttcaattaag aaaagtacac tgaatagtaa agcagtttat gatctctcac aataggactt 73560 agtacaaatt accacctttt aatgggttag aacccatctt atattcacat tttcttaaaa 73620 gtaggtgaga cataacctta ctcatgtcct tacttttttt tttttttggg atgaagtctc 73680 actctgttgc ccaggctgga gtgcagtggc gcggtatcag ctcactgcaa cctctgcctc 73740 ctgggttcaa gtgattctcc tgcctcagcc tcctgagtag ctgggattac aggcaggtgc 73800 cactacacct ggctacattt tttattttta gtagagacgg ggtttcacca tgttggtcag 73860 gctggtctcg aactcctgac ctcatgatcc tcccaccttg gcctcccaaa gtgctgggat 73920 tacaggcgtg agccaccgca cccggccctt actcttaaat tgtaagttat caaactttag 73980 tgtctagcat tttctcaact ataaatcttt taccaaatat tcttgtgtac ctatagaatt 74040 atgaatatgc agtaattaac ctcattgaga ttaatcacaa aatcaacact agcaatatta 74100 actgtttata ctgcatttta ttttatgtat ctaaaattta ctaacagtac gactgtatcc 74160 agtacatgga cagatactgt atccagtatc catcatatct cctaacttgc cttcaaacat 74220 ctgttggctg gttaaaaaat tttaatcttg gagatgaaaa tttaccaaaa caggatatta 74280 aatgtgttca ggttattcca gctattccaa acagagtttt aaaaatggtt ttgaaaaatg 74340 caataatcat tgaaataact gtaatacagc acaatagtag ttaaggtaat aatactcatt 74400 tggacaatct agtctgtcta taaaaaataa aatctcataa attaacgcat caggtcaggt 74460 tgccctagag cattgttttt ttcaaacttg tcacctgcaa ctcattagtg ggtagtctaa 74520 tccatttagt ggtttgcaat cagcaatggg aaaatcagaa tgcattccac aaagtaatgg 74580 acacctactg ttttgtgaaa cttctgtttc aattagatat cagacggata tgtatgtact 74640 gggatgctat gtaaaatact agggattgca gtcaaagagt ttgacaaaac tagctgaaat 74700 tatcttctgg gtatcttcca actttagggt cccattctgt gaatttagtc tttagattta 74760 aataatgtct gttcttgttc aacacccatc tctaatattt acaaaatcat ttttaggcca 74820 cacagtttga gactgttttg ttgtggaaag atcaagagtc agtcagaata caccttacta 74880 gtcccacctc tcacttacca taacttttaa cctttaaact ttagcaagcg attcaattaa 74940 gcctcagttt cctcaacata ctataagttg tgaaggctta ttaagaatat atgagaaaga 75000 gtgttacctt ttaaaacaat tttgctcttt gaacaaaaga tttgcaattt tgtgtcccca 75060 aaggaacttg atatagacta gttccaagat ctagagtcaa acaaatgtag atgtgaaaat 75120 aaccttggag aaaaaaaaat agttccagtt ggaaacctgt ttcaagctac ggagtatata 75180 gaattctgag gagactaaaa ttagaattaa catcttagct caaatgtggg accaggccaa 75240 cattccatat tgccatgtaa tccattctga gtttccttat gccagttccc aactggctag 75300 tgttaaagat gtaagtcagt gtttatatgt acctttacat ccaaaggtat acttgctttt 75360 atcaaatata atgtattcca aagtggaaaa aaaaaaaaag attatctggt atttagacta 75420 tgcattctac agcttttccc cactaacatt catacatgag agctgactcc tcatcatcaa 75480 tgtaaaacct tttaaaggac gtggtggaga atttctacag gattgagaag ccctgtgttc 75540 tacctagtct cagctctacc taagacatgt caaatgacaa ctgaagcaaa tttatcttta 75600 ttatccataa gatgttacat gcctgtccac ttccactgat ctctattcta tgctctccac 75660 cttggtgcca aaagaatgta atgcaatgca atatgttcta ttgtaaatgt aaacatacaa 75720 ctttacctat ttcatctgta aaataagcat aatactatag caataaatta atgtttgaac 75780 tgcttagatt ccctgcataa agttagtgtt taaaagtact agctgttgtt gctgttattt 75840 tattggttct aaaactctct tcaatgatga ccaataattt tttttttagg attatgagtg 75900 atttttattt tccttattct tttccatatt tttccatttt ttacaacaaa tacatttttc 75960 agagtcagaa tatgttcgaa tataaatatg taaagagagt aatttgaaaa gtagttggta 76020 actgaattct gtagacaaaa attttgttat tacctatttt agattaccat tctgctacac 76080 ataagtgatt tcataaaata ctgtgccact taaaaataaa ggccgggtgc cgtggctcac 76140 acctgtaatc ccaccacttt gggagaccaa ggcaagcaga ttgcttgagc ccagcagttt 76200 gagaccagcc tgggcaacat gacgaaacct tgtttctaca aaaaactcaa aaaaaaaaaa 76260 aaaaaaaaat tagtggggag tggnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn 76320 nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn 76380 nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn 76440 nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn 76500 nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn 76560 nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn 76620 nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn 76680 nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn 76740 nnnnnnnctg taagtcagaa gttgttttaa atgcattaga atatttgaaa tttggaagac 76800 tttgtcaaaa cattctaaaa aggagaatgt gcatgcatgc ctgaatttat ttggtataca 76860 gatgtgaatt tttaggtatt tttaaaagta cagcgtatgt tgtatttatt taatatggac 76920 actagcaaga gacagagatt actggggaaa aataaacaaa aacatcctgg atataatcat 76980 agctacctct tcactgcgta acttcctcct ctttaggact cttgacttca tcaattgctg 77040 gataaaatga tttttaattt ctgaactttt taattggcca tgatgaagaa atcctagggt 77100 gttcattttt ttaaaaaatc tgacctgata tcaaagtatt tgcagaatac ctagcaggat 77160 gacatcttaa tatcaaaata tggtattact agacttacag gaatcaaaag gaaaacctcc 77220 tcacttaaaa tcttagtttc ctgagctatt acatcaaacc cattcataat ttaaaaaaaa 77280 aaaaatcttt aattgcatga atatttaagt agaagcagta ctcagataag agagacctct 77340 aacacttaag aatgcctggg atttctaaga aaggctagct tcaactactt cagtcaactt 77400 gaggcttaaa ctattgcctg agatttctag gttatccaga ttaatttttt catgttcact 77460 ataaacacat gaagaaaagt ctgttacatc tcaaatgtag tttaaatgtt tgggtaatac 77520 caaatcacat aatcacgtat gtccatgaga cctggaatcc tgacttctac ttccaattct 77580 gccattaatt tatgtaggct agaatctctt ttagatttca ttttcctcac atgtaatact 77640 aagaagtttg atgtttcatt gtcttaaatt attatataat gctgaggatc tatgtatata 77700 taggcttcat tctctcattc agtttctgag aaattacttt gagggcataa actaagaata 77760 tttcttggtt tcatttttta tttcaattag aataaatcac aagaacaatg gaaattacat 77820 gttaaccaca atatactgta tgtgtaagat aaaattaaat atacctagag cagcacagaa 77880 taatcttatt tttaaagctc tgtgagtcaa tgaatgaata aaagaattaa gttcgtgttt 77940 caataataag agtgttcacc aacgctggaa gctgggagct gaaaatgctg gaagctgggt 78000 tagactgggc tattagaaac cagatgaaaa gggccagtga ctttcagagg ggattttgca 78060 gaacctcctg gtagtggggc tttttatttg tgccaatcac ctttatttgt gctaattcct 78120 atttttgaac ttccctattc aattccacat ctcagccatt ccttttggtt tttaggtatt 78180 tatgtgaaat tctagaactc cctgactaat tggaaccaag tttcacacca ccatcatcct 78240 ctattccaag cttgctgccc ccatgatcct cttaaaaatc tgagtttccg aaagacacat 78300 acttgtatat caaaatggcc ttcctttctc tatgtatgct cacatacata catacataaa 78360 catacatgca caaacacccc aacccaagat gtaccaaaag ccaccttccc aaatattgga 78420 gtctggcttt atcaaaatat ctgtggagta ttaccagaaa tacagattca taggctctac 78480 aatacagctt ctaatctaaa cctcttaaag gatagggccc tggatttttt tttttttaga 78540 acaattttca cgttcagatg tgaaggcagt ttgggagacc tcatgatggc aatactatgt 78600 tcttccataa acttataacc tctatcttct cctttaagaa gtaatttaaa aaatcttaat 78660 acatactatc cttggaagtg cttcatctaa gaaaaatgag aaattatcta cttgtaaaag 78720 aacacgcaaa tgggtaaata tgtaaaaacc tcatcacatt taggagtgtc ttcattcaat 78780 gaaaggtgaa gtctaagctc atgtttatca ctgtactgtt ttctaaggaa caataacaaa 78840 aagtactgaa agtcagtcct aggggaacta tggcagtaag ctaaacaggg gtagggtggg 78900 ggtgttctta ggcagttcta aagtgtttgt gaagagacaa tttatattct attgattcta 78960 aaattcactt ttcttttttc acattatctg tgaaatcaga ttataccata caaatgacag 79020 catcttacaa tgaattgctg gtatttttct gtcttagcag taataaaatt atagtgtttt 79080 ctacaatcag agattaaaat actacaaaca tgaattcttc tcttgtcatc aaagacaatt 79140 tctctaaaaa cctcaggaaa aaagctgcta gtctgctttg aatatcacaa tatacaaaag 79200 caatgaatat atttttcttt tttaaaaaaa tccataatta ttaattcaag ttaccactcc 79260 tcaacagaaa acatacaaga gtctcatata tgaagtcact attttctggg cttgatttct 79320 aaactaagga gtgaactctt ctttcagctc ttaaagccga agatcccata attttattta 79380 tcaatattaa gcttaccaca aagtttctca tttcttcttt tctacccaac gctgctatac 79440 agttccaaaa ttagcaagtc ataaaaaagt ggccaatagt ttgttcactg tgatatataa 79500 gaatgaggct taaaaagcag agattcttgg gaaataaggt cttgaaaaac tcatcactac 79560 ttttgagctt tcacatgaga gaataatctt tttttttttt tttttttttt tttgagacgg 79620 agtctcgctc tgtcgcccag gctggagtgc agtggcgcga tctcggctca ctgcaagccc 79680 cgcctcccgg gttcacgcca ttctcctgcc tcagcctccc gagtagctgg gactacaggc 79740 gcccacaacc gcgcccggct aattttttgt atttttagta gagacggggt ttcaccgtgg 79800 tcttgatctc ctgaccttgt gatccgcccg cctcggcctc ccaaagtgct gggattacag 79860 gcgtgagcca ccgcgcccgg cgagagaata atcttaaacc actttctact atagaccttc 79920 tactatgtgt tactaaaata tgtggcttta tcataatcat cacctgctgt gaatacttag 79980 ttcaaaaaat tacgcaggtt atcaatttta cttctaagac ctattttgat gctggttttt 80040 ccagtgtttt cacattctgt tatttaaaaa aaaaaaaaaa aaaaaaaaga aagaaaagga 80100 agaagagaaa gcaagggaga aagttagtta agagtaaaat ctgcttagtg ggagcattta 80160 gagtccctaa gaagcttctc agtgagcatc atctctttct actttaacag tttattaaac 80220 tgcctaacac acatgacttc tgaagtgaac tgcttttgtg ggcaggcaat attcaagtac 80280 atatactatc tagtgaatcc tgatttataa taggccacac catattatct agttttgata 80340 taattaagca gaacttgcta aaaaaaaaaa aaaaaaaagt taccataatt aaagagctca 80400 cagttaattt tatactaaca cctgagaagg ctttaaaagc ggttgtttcc ttaaaattct 80460 agaatagaat ttaagaaata gaataaagta tacaccaagt acttaacttt tgttgtttgt 80520 taggcttgct ttactagaga aaaaaacggg gggactgagg aaaataagac tgagtagact 80580 tctgagcaga agacagataa ggaaggtaga caattttttg aaccctggaa tgaatcttac 80640 agtgtaattt cattgctttt aaaggctaga catagctttt gatgaagaca gcagaaggga 80700 tctcacctca agaagccaaa cataaagtat gtagcttcgg catttgcagt tctgctccaa 80760 caatggatag tcatagacag acctcaacat acctttcata aaacatcact cacattctta 80820 taaaataccc tatcattctg ctaaactatg taaagcaagg tgctggctgc cttatgatca 80880 gtcgttaagt gtattaatta ttcatgtgtc tcaaaactat gtaagtgaaa taaaaagggt 80940 accagaaagc aagcaataat aatgacttca ggcagttaaa gccccctttt gtctctgcta 81000 gaaaaccacc cgagttgctt aaataatgca gaatctttct ccaccactat aaacatatct 81060 gacattaaaa acaaaaacaa aaacagtaac aaagaaaaaa acacacaaaa tctctgcaat 81120 ttgtaatttc tgagatgtca actttttcca ctgggctata gttttatgaa ttctcaaatt 81180 tagacaattc taaaactaaa atttagacat tctaaaacta aaatacattt taaagtaaaa 81240 atcacatttc ctagttgtgt cagacaactt tctctactag tatactatag tattattaac 81300 taccttaatt ttggttgaca ttaaatttta cttgaagatg ataaaaaagc agcaatgaca 81360 gggataccta atactagaaa tacaataaaa ctctgagaca atacacctgt gacaaatgta 81420 aattctggta aaatgtgact gacaattggt ttctgtcttc tggccactct tatattctta 81480 aatagataca ctaaaaataa tcttttgtgg agaaaagcaa agcaacaaat ggcaacccca 81540 tctggaaaac caggaagtta agacgagtac ctgagtttcc agtatttccc tgctcgatct 81600 ccctgcactt gatgttacag gcaccaccac gaatccccaa atttttggaa tagctgctgt 81660 tttccagaag ttccaagacc cagagttgtc tctatgaatt tttaagtggg aagaaactac 81720 cacagccagg cagtgccgtc catacaggga tattctaagt ggcccagcag gactcaactc 81780 ttactggcaa caggcgctgg tctgccatgg tcacttcatc aagttcacaa taaaacaact 81840 ctgaatttta catgatggaa ttttttggac actacctata attttatggt atagttttac 81900 tgtaccattt ctcccagttc aagacttcac atccacactt attactgggt atctccacat 81960 ttctcttgtt ctggtctttg cccaacactc tattctcttc tgaatgaaag aaactttgga 82020 tctagtattc aagatttaga aaacccactc tttttcaaag atagagtgag cattatataa 82080 tacaaccgat actttgtaga aaacatctat aaacttggac aggaacaaca aagtataata 82140 cttatatcta agatcagaaa tgtccatgtg ttcctatgct atatggtatt tttttcagtc 82200 acttttaaaa tgaattcact gaactgtatc atgatatccc cattactagg tttttaatct 82260 agcagcccaa cttacccgga caagtgcatc atctatgata tggtcacgtc taactttgag 82320 tctcaaatat ggattcaact gctgtccttg aactaagctg tagagaacag tgattcttcg 82380 ttcactgtac atgcgaattc tattgtcata atataatccc aaattctttg tgacagcatt 82440 taatataaag ggacatgtca taaaagagaa tttgttctct gtttctactt tgaaaaaagt 82500 ataatcttta tccatttcta gaacctcatt cagtggttca ttaataaact cttcaaaagg 82560 gataagtggt tttcgacaat ccagggtttt aacaccaagt tcagtttcca gggggtccac 82620 tcgaggacct ttcttgtttc ttctttcttc tcccaaaagc tcctgaagtg tcagctcact 82680 ggattcaggg atgggctctt catcatcttc ttcattgtga tttgtgtcca cttcccctcc 82740 cactacattt gcatagtaaa ccattttcaa gcacttcgaa gcagcaacaa tggcatcatc 82800 atcgttcact agatttcgac tgttaaattc attgcttatg actttgtaag taataagttg 82860 ctgaaatgtc tccatcattc tccgaatctg gtctgcattg tatttagacc acagtctgat 82920 cagttttcct tgggctgcaa ggggtagctt gctcattgct ttgcaaaata atggcaaagc 82980 catttccaga tattcaggac tgtggagatt tctattctcc attacgataa tgaacaaatt 83040 cagataatta ggatctcgag agtatacatt gtgatacgtc aagtcacatt ccacgttagg 83100 tgacaaatat acaagtgcat tgagaaaggc agtttcaatt ttttcattag acagcaatct 83160 ggtgtagacc cttctaatgg catcaatatc cacagacaca tcatcagggc ctactttctg 83220 caaattgttg tctccctgtg agctatcacc tatccttgag gaagatgctt ctgagtcttc 83280 ttccatagca gcagcagaac atgcagcttt ttccttttca tcttcatcct tgtcttcatc 83340 ttttgcttga agagatttca gttcttcctt ggtatgttgt ttaactttcc ggaagctctg 83400 taccaatgcc tcagcactag aaaaaactct tccaataaca cgaattaaag gggaataatc 83460 ctctctttct ctacataatt caagaatttc atataccttc tcttctgtta agtaagtcac 83520 atctagaaaa tcagaggaaa aaagagaaca tttattttca taatatgcat gtttaccctg 83580 ttgcaaaaag ttctaataaa agtaaaacag ccaaacattg tagtctcaac atcatttatg 83640 atatacaact ctaaaagtat ctaatactta gattcagcaa acaaaattca atgcttacct 83700 atttttttca atgaactacc tacaccaatg acctcaccca tgcttttaca ttctttcaac 83760 aatgcataac tcttaatgag atcaggagag tttaaacttt ctttataatc aagatatcta 83820 ttaatgtata gctttattta taaatatgaa ccaatatgtc atatactgat taatcataat 83880 acagctctta aaacctcact gtagaacaga aatactacta atcttctgag agttttcttg 83940 tttcagtact ccgttctcaa aagactgaga aggcaaagtc ttaaaagaaa ggttccttca 84000 gcatctatgt atgtattaaa agaaaactgg ttcattttgg gtcttcctag tttgttccag 84060 ggtagtcatt ctgtgagtga ttgagaagaa tataccattt ctcatcagct cttgagcaga 84120 aactgctttc tgcagccagc aatcaggtta gactaagtct catagagtga cagaaaatag 84180 tttttgagca atgaaaacag tgcgaagaag gcaacttatg agctggcaag cactgcagag 84240 actatgtagt catcaaatct atttcctctt ttcctgggca cagagttgga ccacatttcc 84300 caactttttg agataagtgt tattttcagg ccaatgcttt cccccttctg gctaacagga 84360 tgaaagatat tttattttac aggtaaaaac aaatgatata ttttgtgtac tgaccaacat 84420 aatactgaga atagtcttaa ttctcccttt catcaataaa gtgacatact tatcatcatc 84480 agattaacta cttaaggtgt taattttaga ggcacacaat cctacctcca ttgtgccaaa 84540 cataccttta tacatgtact atgcaacatg tagaattttt aatgactccc acctctgcta 84600 taatatatct gtttcacaat gaaagacaat ataaaatgta agtgatcatt gaatggtctc 84660 caaaaattga accacaaaaa taccaaattt tatcatacta aggatctgat ctgtggccaa 84720 gctacaagag tgtcaacact tgcagtttct tttatgggcc ttaactcttt aagaactaat 84780 tctcaggttt gttctattaa gaatatataa gcatcttttg ctaaacatca gtaacctttt 84840 ccccaaaagc gtaaaaccac tggaagtcta tttctcatta ttttcattga aaatttttat 84900 aataccttct tccaagacaa tgcaaaaccc ctatctaatt tcccaaaatg taacagaaaa 84960 ttaagacata aaacactttg cttcctgagc aagtcataag cttaacaaag acttgctttg 85020 catgcagtaa tatggcctgt cctagggatc acgattctag actcacatgt cctttgttga 85080 tatgtcatgc tttcggaaca tcttcaagtg attctgacag tctactaatc ctatatagaa 85140 tgtacctata ctttttccat gtagagtttt ttgttgtggt tgctgttgtt gtttgagatg 85200 gagtctcgct ctgtcgccag gctagactgg agtggcacga tctcggctca ctgcaacctc 85260 tgcctcctgg attcaagcga ttctcctacc tcagcctccc gagaagctgg gactacaggt 85320 gcacaccacc acagccggct aatttttttg tatttttagt agacacgggg tttcaccatg 85380 ttgactgggc tggtctcatc tcttgacctc gtgattcgcc cgccttggcc tcccaaagtg 85440 ctgggattac aggcatgagc caccatgcct ggcctgtagt gtttaatatg ttaaactgaa 85500 tttttcagat atatagataa aaattagtca aaaaacactg taattagata tgaacattca 85560 taaagtttgg tttactgata gaggtgttct actgagaata tattaaataa gacatttttt 85620 gtaagatttc ttgtgataaa tgtgtccctg aaaatactca atcttttaaa ttctgcactt 85680 aaaaaccttt tacacaacaa gagtttggtg cagactactt aatacttacg caactttgtg 85740 attagtgtta ataaacataa ttaataatca aaataagagt actagtgcag agaaagcatt 85800 tctaatttct aatatatgat agtaactgta aaacactgca aaaacaaaaa caaaaacaaa 85860 acagtaaaga acagggaata gtaccagtag cagattagaa agcaggaaaa aggaaaggtc 85920 aaaactgcta actaatgcag acttcagcaa aaagaggtgg gggcataaag accggataaa 85980 gccacacaat aagcatctct aagatggagc atgtggccaa aagagcagat gagtacattc 86040 ctcatgtatc acaccccccc cagctggctg cattccactg tgccagcact ctgcgttcag 86100 ttactggtac tctgtggtgc acacttactg gagaactgtg tacaataaag tcaatgcagc 86160 ttccacatta tactgacaca ctatatatat agacatttac ctatttttcc acagtgtgtg 86220 agctaattca tgaaacagaa ctatacactc tgaagcaaca aagttgtgta aagtgacgaa 86280 aataattcta ttgtggaaac agtagaggtt ataacacaat gccacttcat taattctttc 86340 aaacttgatt cagatgatgt tactgaaagt tttagaggca aatgcctcta aaattctgtc 86400 acttacacgt cataaacaaa aagctttctc tcttaaaata caattgcctc tgcgtgtgta 86460 tgggggtggg ggtgcagggg cgctaagccc tggcagtcat tcaaaaattt gattaccgtg 86520 ttactaatta cattcactga ggaaaataac ttggagtttt agtattagcg acaaggtaat 86580 cgaatcctga attttggaca caggaccatt taaaaaacaa aagacctgag tgaagattgt 86640 cattggtagg tcaccaccct tggcagcatg actgtaccaa atgtttgtga ggagagtgag 86700 aagcatatat ttgaaggaaa tgtagaattc tcacataact atcacaaaat tttgtcttgc 86760 cttctaaaat ggaaaaaacc cactgcttcc tcttcctact tctttcatca catcatcctg 86820 aggttccaga actcatgcca gatactgagt ccagttattc tataacttaa atagatgttg 86880 tggcctagtt ttggagatta actatcaatt aatacttttt tccctaagaa ttttaaaaag 86940 ttcaaatcca tctattaaca aatgaacttt tggcatatga tctgcttcta attagcaacg 87000 attaaacctg taaaatgtag ttattattcc tgtcctttac caaaacaaaa aattggttct 87060 acggtatcaa aatgtcttaa tgtcacataa gaaaaaacaa ataaaaactc atacatttaa 87120 atctcccaca tggttttcag ccaacaattc tcaattaaaa ataaaacatc ttacctttaa 87180 aatcaattct agtgcctttc ttgttcattt ttatctcaga gcaggagttg ttgggggcac 87240 ctttcgagtt ctcaaggtaa gctgagcttg ctcctttctt ggagggatga ggatcacaga 87300 gttttgcatt aatcttataa agctcgaggg ctttaatagc tgctgcatta ttatccatac 87360 gaagaaaagt tggacaggaa gcacaaaact cattcgtgca ggcttcattt ccacagccct 87420 cagttaactg gtggtagtag cgttctatta gatgctttgc agctgctcgc ttcctgtacc 87480 aaacagtcaa acaataagca cagtgattag tatagctgtc atgtacaaag cccaacagat 87540 catcaaggca aaagttagtc aagcactgaa gtgattaacc tgtgtgcgaa gatgagaagt 87600 agaaaatgga gatgcactat ttaccaacaa cccctgacta gtgaaatagc taataaatat 87660 tttctaggat attatgataa agaatgtcaa tgcttactga ctgcattaac agagtataca 87720 ctcctttggt ttaaaagggg ggaggggggc tcgtctgatg gtatatgtgc ttaagttgtt 87780 tagtacaaca gctgaaaaat caccaggttt acagctaaga gttttaggat tctatcattt 87840 taaaaattag cattaggaaa atccagtttt cctttacata atcactattt catttttaac 87900 agtttgtaaa catttgactt acagttaaca cagaatatct atctggaata aaaactattt 87960 ttcccaatta tcaaccacat gggagactta aaaataaatt tgtaagtgga atatccaaag 88020 ctagtgttac actgaaagaa agtggctgca gcctgagtga ggtagatcat gactgtaatc 88080 aatcccataa ctgcgggagg ctgaggcacg cagactactt gagcccagga ggtcaacacc 88140 agcttgggca acctagtgag gctactctct acaaagtgtt attttttttt aaattagcca 88200 ggtgtggtgg catgcactgt agtcccagct acttgggagg ctgaggtgag aggatcactt 88260 gagcctgaaa gtcaaggctg ccataagccg aaattctacc actgcactcc agcctgggca 88320 agagctagac tttgtctcaa aaaaaaaaaa aaaaaaaaaa aaaaggaaaa taaaaaagaa 88380 aaagaggctc caaagtatat aatcttaaat ctaaaacttg tcactaaacc tcctccttag 88440 ttccacatta caagatggag tattttaagt tgcatcactc aaaatcttat attcctttta 88500 ctctgtgaac ttaaagtaca cagattaatg tcctatttca gctgttacaa gagagctacc 88560 aaaactgagg aaggaattat gtgatcaagt aagaagttag atgacattat ctctatattc 88620 aacactaaag agtctgtact tctactaact gatgatgaga acaccataat ttcagtagaa 88680 taaactactg gatccaaaga aacgtaagtc atagctattc cttttggtcc caaattcaca 88740 agtatggaaa taaaaactac gaagaatcaa aattataaga aaaataattc agctaatttt 88800 caaaacattc acagaattat cttactaaca tgtaggacta aatgaccaat ggcagagaat 88860 ttacatcttg ctaatcataa gaaactcagt aacaagacag caagtaagtg aagagacaaa 88920 tgagatccaa ttttgtctca aaagaaagac tttgactgtc taaactatgc aggtaggtga 88980 caaaaagtga taattcacac agattcaatt cattctggtg cttatatttt ttcaaatgtt 89040 ccatgcaaat ttaccactca ctgcatgcaa acagagaaaa aagaaaaccc acaaagcaca 89100 cgtaaaaatt gcataaacat gacttagaga cattttgtta tctatgaagc tataaacaac 89160 ccaacctgaa aattaaaaac tgttatcaca gatttatcac tatgcaaaat atgaaagtga 89220 aaacatgtaa aaataaaagg ggaatggaga atccagaaac tttaaaacat acattgttag 89280 tcttcagtaa agaaagggag ataatgtcat gttctcctaa actacagtga cttccctggt 89340 gaaaatgtaa acaggtattt cctttctgga ggaaaatagt gaatatgtat cgaaagtctt 89400 aaaaacatga ataccacatg aatgagatcc tacttgtgga aaacaatttg acaattttac 89460 aaaaatgcag tttccatatc tgaataaaat caacatgttt aataaaagat tacttaaatg 89520 aactgataat aggtcacaca ataaaataaa aactatcaag attgaatctg acaaggaact 89580 gcctagtctt cctgatatat cactaactga caaaagtcag ttacaaggta gcaggtgtag 89640 gatgaaccca ttgttatttc aaagcattaa tagcattttc tctggacgat gtgattaaat 89700 tagttttaaa acttctttca tcttttgatt tcttatttat tctttccata ataaggatgc 89760 tacttgcata ttaaaaatta ataactataa ggggaaaaca acagttttaa aacttcatat 89820 acatgatttg aatggcccca agatgtatta aattgtctct gatttttaaa aaaattataa 89880 aagtcaaaat actaagatag atatttttaa tgtgagcttt tatactaaaa taacttcccc 89940 aaaacctgtc agatacatag tacttcttta catactacat aataggagag tgatcagcac 90000 aaacagaatg agactgaaaa atcagaagac ctgcattaag tgtcatcctt ctgtccctaa 90060 gtagctgtag gatcctaggg aaataactgt ctgggcctca gttttcccag ctttatgagt 90120 cccttcagtt ctaattttaa gttattttat gtaataggga ggtgaacaag aaaccagtat 90180 ttgttggatg cctgataaca tattacacac actgcggggc actttgacat aggttatctc 90240 atttgagtat catgatactg aggattatct tcagtccaca gccaaagaga gaaatagaac 90300 tggagtcaaa tcaccaaacc cagatctcaa agaaagtaca caaccaagac aagaatagga 90360 gtccaggagt ctttcagctt cagagtctaa gtcattttga ctatactgtt ttgcagaagg 90420 tgattcattt ccaaacaatt attttttaac atgagtaata ctgaagaatt ctatggaaaa 90480 aaaatctcat aactaatgtg caactgggaa aaaaaaactg aagaatcata atgtgaacct 90540 cacatttatg catatatctg ataccacaaa ggtagaccaa atttcttgag gaaatggaac 90600 caccacattc tgcaaagcta atttatctct aattttctga ggacctatgt gctatgcatt 90660 ttatagacat tctcacgtta gaggggaata aaccttaaca gttaagagct tgcattctga 90720 ggccagatgc ccaagttcac atgatggctc tacctcttaa ttaactatgt gaccctgaat 90780 gagttacctg acctttctgt acgtcagttt cctcataatt taagtggtag tatctacgag 90840 cattctcatg atgagagtat tattattctt cacattatcg attgtgagaa aattaaatgt 90900 gttaatatat ataaagtgct cagaacactg cctggcatac taagcactat gaaagtgtta 90960 gctactacta ctattgttgt aattgttatc accctcacaa gtgtatgagt tagcactata 91020 aaccttcatt ctgctgatgc tcagagaaat tacatcaata agtcattcat ctaataagag 91080 atctgaactc agctactaaa tttgagcttt taataactat taagaggagg atatgaaagt 91140 agacccctgt atttgatctg cctttctgtg ccaagttaac aaacagcagc tacactgatg 91200 agacaggact aaaggaagcc aggtcagaaa ctccatgtta atggtggaat caactatatt 91260 aagcattctt ctttttcctc actccaatga caccttaatt tatctgacct catctgtatt 91320 actatctaat ttagggtatg taaaaggcat acaaaattta gagcacataa aggggcctct 91380 atgttggaaa agtatacatt aaacgacttt ttggtatagt tcctgtgcaa ggttaatcct 91440 tgtaccatat ggttcaccaa atcatagctc atgagtcaaa ccaagttcat cacctatttt 91500 tgtatgtctc tcaagcttag aatattgtac atattttaat ggctggaaaa agtttaaaaa 91560 agagtatttt gtgatgtgaa aattatatga aattcaagtt tcagtgtcca tcaagtgtac 91620 tggaacatac ccaagttcat ttgtttataa atatactata tatgatatgc tttggctctg 91680 tgtcctcacc caaatctcat cttgaattgt actcccttaa ttctcatgtg ttgtgggagt 91740 gaccgggtgg gagataactt gaatcatggg ggcagtttcc cacatgctgt tcttgtggta 91800 gtaagtctca cgagatctga cggctttatc gggggtttcc gcttttgcat ccttctcatt 91860 ttctcttgtc agtgccatgc aagaagtgcc tgtcaccttc gccatgattc tgaagccttc 91920 ccagccatgt ggaactgtaa gtccaattaa acctcttttt tttccccagt ctcaggtatg 91980 tctttatcag cagcgtgaaa atggactaat acaatatact atatagttta tggctgtttt 92040 tcatactaca atggcagagt tgagtattct aggcctgcaa aacctaaaac aaataccacc 92100 tgccttttaa agaaaatgtt tgccaaccct taatttagga tgttatttat ctctgccctc 92160 cagtgaccct gccatctaat catttggtct cttaactctc tctttcccct cagcaaataa 92220 gtaaaataaa aggtgtacct ttccccaagt attattaaag aaaagaggag aagagggaga 92280 gagggaaaga gggaaaaaga aagtaaggaa aaggagagga tgcaaaagaa aaagaaggaa 92340 agaaaggaat ttccctgatg aggtcccttt agcaacacct tatcagctgc tcataatcaa 92400 aattcctgga agaggaacta tagctttact tgccataatt tcttcacatt accttgactt 92460 ttctttttac tcaaaaaagt atgttataat gtgttgattt ttaaaataaa aaaaactttt 92520 cttagtcagc aatgaaggtc aagcgagacc ttctagtaag tcttgtaaag ttagacacat 92580 gaaaatactt atccatttca aacagacaat actttccaat ttttatttct atgactgaat 92640 tagtgggaca gtgctacaaa cagaagtcct atggaataag tcatatttgg aaggtcagtt 92700 taccctagac aacttgacag caatcagttt aaaaatggtt tcacctagag ggctgtgtac 92760 tgatgttagc aattaacttt gaaaggcata aaaattaaga tggactgatg atacaaggat 92820 ggttataaga taaagcaatg taaatattaa tggcagaatc taggtgacag gcatatgcgt 92880 gtcagctata aaatctgtgt tcaacatttt ttagttccca catatcagtg agaacatgtg 92940 atatttgtct ttctgtgtct ggcttagttc actaaaaaaa tgaatttaca ggacaattgg 93000 aatataagca atgaatacaa gcactaagaa gatgaggcca tagacacagc tgccagaaag 93060 tgaagatgtg acagtgaaca ctgaacaaat aagattagaa ttacaattag aatcagaaat 93120 gacaaaagag aaatatgaac tgtgagatgc aatataaaaa ctgatggtga gtaaagcaaa 93180 gaataaaaaa taaaaaggga aagattaaaa ggaaaacgtg actataagta gagtgacctt 93240 tatatttaca gaaggtacag cagaatgaac atgtgagaag tctaaaaaac agatataaaa 93300 tagaaacaac tcaaggctta tataattagt ctataaagct aagaaacact gcttagtaat 93360 ttctcgtaag tggagcctct ttattctttc tgggatgttg caaaactcca ttccatctca 93420 aagttatttt taatgtaaaa atttgtaaga gtgagcaatg gtatcctaaa tagttctagg 93480 ccttgtagaa atagattgta agagacatct gtgacatagc tatattcagt acgatgtagg 93540 gtctgttaca atgggatgaa atgaatttag attatttcaa gactaaacct acaattgtga 93600 actctttagt accatgaacc aaacaaaaac ctattaaata tagaacaaga cgattttcat 93660 gaaaaaataa acacaaacaa atcagtattt tcaagtgttt gaaatatagg ttaaccttta 93720 agaactgttt tattcatttt tatagtctca atgtccagaa tgcttgatat atgattaaaa 93780 aaaagtaaaa ttatacaact aaatatttat ataattcatc tgtaaaatga aaatctgttt 93840 taacgtgtca tatttcacag ttaggagaat aaaaacctca aatcaacaaa ttaactttac 93900 atcttataga attaggaaat gaagaacaaa ttagactcaa acttaccaaa aaaaaaaaaa 93960 aaaaaggaaa taacaaatta cagttaaaca aaatagagaa aaatagaaaa tttttgcaat 94020 agaaaaaaaa aaatcaacaa aattaggagt agctgtttca ttgaaaagat caacaaaatt 94080 ggcaaattct tagactaaga aatgaagaga atagacacaa acagcaaaaa ttggaaatta 94140 gaaaggagat acaacaactg ctgccgcaga aataaatagg accataaaag actaatatga 94200 acaactatgc cccaacaaat ttgataacct ctgagaatgg atagacacat caaacccacc 94260 aagactgagt cacaaataca tacaacttct gaatgtacct ataactatca gagattgaat 94320 cagtaactgt ccaacaatac cagggcttca ctgaaaactc taccaaacat tactctttga 94380 aaaaactaaa gaggacagaa cactttcaaa atcattatga ttttgataat catagtaatg 94440 ctaagtaagc attacttaga tatcaaaatc agacaaattt actacaagaa aaaagaatcc 94500 ctaataaata ctgatgcaaa aaaaatcaac aaaataccaa gaaacagaat tcaacaatgc 94560 attaaaaaga acatcctttt gtgatttaaa aaaaggccag atatggtggc ttgtgcctgt 94620 aatcccagca ctttaggagg gcaaggtggg cggatcacct gaggtcagga gtgtgagacc 94680 agcctggcca cacagtgaaa ccccatccct actaaaaata caaaagctag ctacgcacgg 94740 tggtgggcac ctgtaatctc agctactcgg gagactgagg caggagaatc acttgaaccc 94800 gggaggcaga gctggcagtg agctgagatt gcatcattgc actccagcct gggtgacaag 94860 agcaagattc tgtctcaaaa ataaaaacaa aaacactcaa tttgctagaa agatatggaa 94920 attacttcaa aataatgaag gccatatata gaaagaccac agctaatgtt attcaatgat 94980 gaaacaccga aagttttccc tctaagatca caaacggaac aagaatgcac acattcacca 95040 cttctactca acatactatc agaagtcctg ccagagtcag caattgggca agaaaaagaa 95100 ataaaaggta ttaaatgaga aaagtaagaa gtaaaattac ttctgttagc aaatgacatg 95160 atcttatacg ttgaaaactc tagcccacca aaaagaaaaa aaactgttag aataaaggat 95220 acaggatata aaaataaagt tacaggatat aataataaag ttacaggata taaaaaccaa 95280 cattaagagt tgcatttcta aatactaaaa atgaagaatc caaaaaggaa attaattttt 95340 aaaatccatt taaaatgaaa tcaaagagta aaatacttag ggaatatttt caacaaggaa 95400 atgaaagaca catacattga aaattataca acataggcca ggcgcagtgg ctcacgcctg 95460 taatcccagc agtttgggag gccaaggtgg ggggatcacg aggtcaagag attgagacca 95520 tcctggccaa catggtgaaa tcctgtctct actaaaaata caaaataaat tagccgggct 95580 tggtggcaca cgcctataat cccagcaact cgggaggctg aggcaggagt atcacttgaa 95640 tccgggaggc agaggttgca gtgagccgag atcgcgccac tccactccag cctggtgaca 95700 gagtgagact ctgtcccttc tcccccgccc aaaaaaaaaa aaattataca acaatgctga 95760 aagaaattga agataatata aataaatgga aagacatcca agtttatgaa ttggaagatt 95820 tagtattgtt aagatggcaa tactactgaa agcaatctgc agattcaaag caatccctat 95880 caaaatccca atggcatttt ctacagaaat agaaaaaaaa aaaaatctta aaattattac 95940 ggaatcttga aggaccctga atagccgtaa caatctggac aaaaaacaaa gctagaggcc 96000 tcccattccc tgatttctaa agatattgca aagctacagt aatcaaaaca ctatggtgct 96060 ggcataaaga cagatataca gaccaactga gcagaagaga gaacacagaa atagggaaaa 96120 gaggttcttc aacaaactgt gttgggaaat ctgaaatcta acatgcaaaa gaatgaagtt 96180 ggagccttat cttacaccat atacaaaaat aagctcaaga tggattacag acctaaactt 96240 acaacatcaa actataaaac tactacagaa aacatagaga aaaagcttca tgacattgga 96300 cttggcaatg atttcttgaa tagatcacca aaagcacaag caaccaaagc aaaaatagac 96360 aaaccgggga tacataaact caaaaatttc tgcaaagcaa acagtaaaca gagtaaaatg 96420 gcaacctaca aaacaggaga aaatatttcc ataccatgta tctgttattt ggttaatatt 96480 cagaatatac aagtaactcc tacaattcaa caacaaaaaa tctagttaaa aagtagacaa 96540 aagacttgaa tagtcatttt tccaaagaat gtatacaaat ggccaataag cccatgaaaa 96600 gatgctcaac atcactgatc agtagggaaa tgtgaatcta ccatctgaaa ccattaggat 96660 gaccaccatc aaaaaaacag aaaataagtg ttggtgaaga tatggagaaa ctggaaccct 96720 tacgcaccat tggtgaaaac gtaaaatggt gccaggcact atgaaaacaa catgaagatc 96780 cctcaaaaaa tttaaaatag aactacctcc agttccacat ataaagagct tggaagtcac 96840 cactccattc taacaggtaa aaaatgacaa actgaaaaac aatcaaatct gagataggat 96900 aagtgaggtc acagggcaaa taactgcctg taagtgagag cgaaggacag gtgaacacat 96960 agcatcacca tttatctgag atgaaaaaca caagcagaaa cctccacagg gtaggaaatc 97020 ctgaagtgta atggacaaat tgatgaaggc tcagtgtgga caactccgaa agctaaaaac 97080 tccacagtta cccaattata gggggacccc tacaattttc taagttttac atccaggcaa 97140 ttgaccagct tctcacagtc aatataggag aaaaattctc aaccctcagc aggggagaca 97200 aagagaaacg attttcaagt acaccacagt attctggtct taacaaggtt tgtcctcagg 97260 agaaactaac cagagcctga cctgctgatg ttgtagcaaa gccaaaatga tgtgggggaa 97320 gagaaataac ccaactccac gccattatag ctatcttgtt ctatctaagg gaatgggggg 97380 gtggtgtggg actgagaaac acttgtgaag ttcacagtcc agaggcataa gctcactaaa 97440 agactgacct aatcataaga ctacagaact cttctcctct tcctacacct tacaaccaca 97500 ttactaaagg ttcatttaca acagttcctt ttacctagta catcgtgtcc aagctatcaa 97560 taaaaaaatt acagggcata ataaaaggta aaaaacaagc atcaggacca aattcagcag 97620 ggatttggaa ttatcaaact gggaatctaa aacaaccatg attaatatgc taagggccct 97680 aacgaattga ctaaacaaca cgttaaaaaa aaaaaaaagg agagatgaaa atcctaagaa 97740 tgaaccaaaa ggaaatgcta gagataatac aaaaacaaaa acaaaaaaca gaacactgta 97800 agagaaatga agaatgcctt tgatgggctt attagtaggc tgggcatgga tgaagaatct 97860 ctgagcttga aaatacatgc caaaaaaact acatctgggc ataaaacgtt gttaactaca 97920 gaaattcaag gataagaaaa aaatctgaag taagccagag ggaaaaaaat cactttaccc 97980 atagaggaaa aaaagaaaaa aaaagaaaaa atacatgtga cttcctacaa gaaaaagagt 98040 ggggtgaaat atttacagtg ttgagagaaa aaattcataa acgaagcatt ctaccttgtg 98100 agattattac tcaaaagtta actggaaatc tacatataca gagcataaaa agaaggaaac 98160 acggaaagta aaataaaacc ttttattttt cttatactta attatctaac aaataagaat 98220 ttgttcaaaa taatgtcaac aattgtgctt acgcatacag acgctcctaa acttacttat 98280 tgggttgtgt cccgctaatg ccattataaa gtgaaaatat cacgaaaaca caacttatcc 98340 aaatttgtgg gatacagata cagtgaaagc agtacttaga aagaaacata caacactgat 98400 gcatttatta gaaaagaatg atctaggcca ggcgtggtgg ctcacgcctg taatcccatc 98460 actctggggg gctgaggtgg gtggatcacg aggtctggag ttcaagacca tcctggctaa 98520 cacactgaaa ccccgtctct actaaaaata caaaaaaaaa aatcagccgg gcgcggtggc 98580 aggtgcctgt agtcccatct actcgggagg ctgaggcagg agaatggtgt gaacccggga 98640 ggcagagctt gcagtgagcc gagattgtgc cactgcactt aagcctgggc aataaagcgt 98700 gactccgtct caaaaaaaaa aaaaaaaaaa aagaaacaaa aaaacaaata agaaagaaag 98760 aaaagaatga tctaaaaatc aattatctga gctaccacct tatgaaacta gaagaagcaa 98820 attaaatcca aacagaagta ataacaatta gagcagaaat caatgaaatt gaaaacaaga 98880 gaaaaatcaa agaaatcaaa aactggttct ctgaaaagat caacaaaatc aataagcctc 98940 tagtcaggcc aactaagaaa aagagacaaa ggacaaaata actaatatca gaatgaaaag 99000 agtacacatc attacagatc tcatgggcat taaaaggata atcaagggat attatgaaca 99060 actttatggc cacaaatttg gtaacctaga cgaaatgaat caatttctta aaagacacaa 99120 tctattagaa ctctaagaag aaacaatctt gattaaaaag catatattat agaaattaaa 99180 catgtaatta ataatgttct aaaagagaag gcatcagacc cagatggagt ctctgatgaa 99240 ttctactaaa catttaagga agaaaccaca ccaattcttt acaatctctt tcagaagaca 99300 gaagcaaagg ggatgctcct atctcattgt atgaagtcgg tcagcattac tctaataccc 99360 aaaccagaca gacattatca gaaaactaca gaccaatatt tgtcatgaac aaagatgcaa 99420 aaattgtaaa caaagtatta gcaaactaaa aacaacaaat ttctccacca gcacaaagta 99480 ggatgtatcc caggtatgca agactggttc aatattggaa aatcaattaa tgcaattcac 99540 cgtatcaaca gattaaagaa aaaaaaatca catgaccata ccaatagatg gagagaaata 99600 tatgacaaaa tttaacaccc actcatgata gaaactagta aactaggaat agagggaaca 99660 ccttcaactt gataaagaac gtttacaaaa aacatacagc taacatcatc tttaatgatg 99720 agaaactaga aactttctca ctaagatcag gaacaagaca ggaatatccc cacctcacca 99780 cttcatactg gaagtcctag ctaatacagt aagacaagaa aaggaaataa agggtatact 99840 aactgggaac aacaacaaca aaaatgcctt tgtttgtaga tgaaatgact gtatgtgtag 99900 aacagataca ggaatttgaa aaaaagaaaa acaacaaaaa cctcctggaa ctaataagtg 99960 attacagcaa agctgcagga tgcaaggctc atataaaaaa gttaatagct ttccggtaaa 100020 ccagcaacaa ataagttgaa tttgaaatta aaaacacaat accattttac attagtgtgt 100080 cccaaaatga aatacttaag tatagatcta acaatacaag gaaaaatttt ttagaactct 100140 gatgaaagaa atcaaagaac taaataagga agagctattc catgacccag aagagccaac 100200 tcaatattga cagaaaaagt cagatggaca ctactgactt caagatttac tgtaaagctc 100260 cagttgtcaa gatggtgtga tactgacaaa agaactgaca aaacagatca atgaaataga 100320 atagagagcc cagaaatgga cccacatagt caaaggagca atggcagtat ttgacaaaga 100380 ggcaaaggca atacaacgaa gaaaaaaaaa atagtctttt tcaataaaca gtggtaataa 100440 ctgaacatcc acaagcaaaa aaaaaaaaaa aaaaaagagt ctagacacag gtcttacacc 100500 ctttacaata ataaactcaa aaataagcca gagaattaaa ggtaaaactc aaaactataa 100560 aactcctaga ggataacata ggagaaaatc tagatcttgg gtttggtgat gactttttag 100620 atacggcaac aaaggtacca accatgaaaa aaagaactga taagctagac ttcatcaaaa 100680 ttgtctactt gtttcttaaa aattgttgtg tcttttgcaa aacacaatgt caagagtatg 100740 aaaagacaag ccacagacag ggaggaaata cctgcaaaag acacatctga taaagaacta 100800 ttaactaaaa tgtgtaagga agttgggcgt ggtggcttac atcacagcac tttgggaggc 100860 caaggtgggt ggatcacctg aggtcaggag gtcgagaata gcctggctaa catagtgaaa 100920 acccatctct actaaaaata caaaaattag ccaggtgtgg tggtacacgc ctataatccc 100980 agctatttgg gaggctgagg caggagaatc acttgaaccc aggtggcaga ggttgcagtg 101040 agccgagact gcgccactac actgcagcct gggtgacaga gcaagggtcc gtctcaatag 101100 atagacagac agacagagag acagatatag tgtaaggacc tattaaaatt ccacaagaaa 101160 acaaacaacc caattagaaa atgggacagc caccttaaca gacacctcac caaagatacg 101220 cagatgtcaa ttcagcatat gaaaagatgc ctcacacatc atacgacgcc agagaaacat 101280 aaatcaaaat tataagatac acacctatca gaatggccaa aattcagaac agtgataaca 101340 ccaaatactg gtgaagatgt agagcaacag aaacactcgc tcattactgg tgaaaaatgt 101400 aaaaggatag agtcacatta gaagacagtt tggacatttc ctacaaaact aaacattttt 101460 gccataagat ccagcaaatg cactccccgg tatttacaca aagtcactga aaacctaagt 101520 ccatacaaaa acctgcacac cgatatttac agcagtttta ttcataatta gcaaaatgtg 101580 gaagcaacca caacaatgtc cttcattagg taaatattca ttcacaaact gtgatatgtc 101640 cagaaaatgg aaaaagagag gtactaacaa cctatgaaga catggaagaa actttaatcc 101700 atattagtaa gtaaaaatag tcatgatgaa aaggctatat actgcatgat tacaagtata 101760 taatatgctg gaaaaggtaa agctacagac acagtaaaag gattggtgac tgccaaggag 101820 tgggagggaa cgaaagataa acaggcagaa cacagaggat tttggggcag tgaaaacatt 101880 ctgtatgata ctataatggt ggatacatgt cattatactt tgttcaatgc cacagaatgt 101940 acagcactaa gaacgatccc taatataaac tacggacttt gggtaattat gatatatcaa 102000 tataggttca ttggaaagac atgtaccact ctgatgggag atggaccttg actatgagag 102060 aatctataca tgtgtggaag gaggtccagg gaaaatctct gtaccttcct ctcaattctg 102120 tgaacctaga actcctgtaa aaaaaaaaaa aaaaaatttt ttttttttta aatagaacac 102180 atatgatcca gtaatccaac acctgggtat actcccaaat gtgttaaaaa caggttctca 102240 aaaaaatatt tgtacaccca tgtttatttc aacattacaa cattcaaaag tggaagaaac 102300 ctaaacatcc atcaacaaat ggttaaagaa aatgtgatat acatatgtaa caaaatgtta 102360 ttcagcctaa aaaaaaaaaa aaaaaaaaga aagaaatcct gtaatatgct acaacacaaa 102420 tgaaccttga ggacattatg ctatgtgaaa tagtacagtc aacaaaagac aaatacttaa 102480 tgattccact tatatgaagt aactaaaata gtcaaatttt agaggcaaaa agtagaatgg 102540 tatttgccaa ggaataggaa gaagggggaa aagaagagtt gttcaatgaa tgtagtttct 102600 gttttacacg atgaaaaagt tctagagatc tgctgcacaa cagtgtacac acagttaacc 102660 acaattgtac tatacacttc aaatcattaa tatcatccag tttgttgttt ttgacaattt 102720 ttaaaaatct accccatttt tttctttacc tcttatataa actgataaaa acctgtttta 102780 tcctaatcaa ttatttcatg actactgctc cccagagaaa aaatgacatg tgaaatacta 102840 cgacttatcc atctcctggg tctgagcagt acatgtcagg aacaagaggg aactgtagct 102900 ggaagacagt agaggagccg taggacaagt ctcaaagaga aggaagaaaa ggcgcaaaga 102960 aagaaaacaa gtttaagata gtaggaaagc attcaaagac tgcaacctga gataaggggt 103020 tttcactaaa ggttttgggg taaaacagtt tgagttggca tgcctgtaga catgggaagc 103080 agcagtgatg cagaggtgaa cattactgta gataaaacag atgggaattt gagttgctag 103140 ggagtgaggg gttcatcaga taaataaaga tggcagcaga tttgggcaag agtgaagaag 103200 agtaagttca ggtatcagtc ttcaaaaacc gagaagaaac tgagagctca ctaaaggcag 103260 atagaggatg acacaaccag aaggcataag cttcaaagga gcagggattt ttatgctgag 103320 agagtaacag gaatagttca aagcagcagt ggagaacacg aataacattc tgtgtgggag 103380 aagaacacgt ccagagctta ctgtacctat aacctagctt ctgtaactgg aaatgaagaa 103440 tctgctctag acaggtcatc acttttcact acttatttta cttggccttc ctaagaaata 103500 tagacctttt ggaaattatt gacttttggg tctaggacac tatttcttgg tttcctccct 103560 tctctctggc tgtttttcag agacttcgct tccaaatcta gagacatttg tattctccag 103620 ggatcagcta ttagatactt tctcttttaa atttcccttt ggacagtttc atcttctttc 103680 aaggattgag caataactaa atgacttcca aatgtctact tcagtataaa ttctgcttgt 103740 caggctacat aaaatgggct cttccaggaa ttataatgtt taaagaaaga gaaagccacg 103800 tgatttcagt atgacagaga tgactacaga ggaatagcaa taaaaagaga cgcaacttag 103860 cagaggtgaa tcacaaaaga tgactaggag ctgatgacac taagggtggg aagaatgttt 103920 cagatagagg aaaatgagta aaagcacagg gacatgagaa catggtatta taagacaatt 103980 ccaagcactt caagagccta aagttcaaga aaagtttcaa aaatatgaaa atggagaggc 104040 agggagaagc tagatcatgg aagacctcac tagccatgat aagtaattct ttttttttag 104100 ccaaaagagg agtaatctaa taaaagctaa agatcttctc ctcataaaaa cacatgcaca 104160 cttcaggagt gcacatgcag tcttccggaa gattcgtaac ccactatatt cataaaccat 104220 tagagaagaa ctaaaacaca aggagtcact gaagggtttt aagcagctaa gtggctgata 104280 aaatttgcct ttccaataac tgaaaccaaa gtgggcaaaa ctggaggcaa gcaatccagt 104340 taggtaatga ctactgtaat agtccagaca aagaatgtag tagtagcaag aaaaaaaaag 104400 atgaaattga cccaggaagt atttaaaata agtaatttgt aagaggtaaa taagctggaa 104460 aagctagaga taatgggtaa ggtttctggt atgggcaaca agatatgcta caagctgaga 104520 tgttaataaa aacaaaagtt catcagcatg tagtaattta tttatattat gtcactgaat 104580 attcaattat gttaagaggc agacagtagt taaaaacaaa gaactggtga atcaaaaagt 104640 tctgctaatt tggggaaata gcatcccttt tattttcatt aatctctttt ggctttgatc 104700 ctcatttgta gctgacaaga agttctatgt attaaactat tctcattaat gtgtccaaaa 104760 atctcttggg aataattaag acataaatta attcaaaatt cacatgatta caaaaatctc 104820 tccttagata atctcataat atagccatgt tttgctcact ctactttgag aagattcagc 104880 cagaagcagt tcatccattc aagtatgttc ccttacattt gaaacagaag atacaggttt 104940 atatgatgct tcctgtggca gaaaagcagg gcagactgtg actcgtgtca ctcccacacc 105000 cgatgccttt catgggctcc tgtgtctgtc agaagaaagc aaagggcctt aatacggtcc 105060 tggctttcta catccaaatg cattttccac acctcccatc agctaactct acattacggc 105120 aatacagaac ttcttactac tcagtggact tgctctgctg tcttctctga ttacaggtgt 105180 tattcttcct gcccagaaca cattattctt agttatttcc aatcatcctc aaggtttcag 105240 cttatatatc acttttaaga tgattaggta ttcttcctct gtagtctcat agcaaccagt 105300 acctattctc actattatat gttgttgtaa ctgactatca attaaatggg aggctgaggc 105360 atatgaccca ataacttatt tactgttgta tcctctgaac ctagcaaatt acagatcctc 105420 aatagagatt tttcaatttc tcttctgata ctgtctagat aacactgtca attaaaccta 105480 ccttcctcta attattcgac cttgaaggga aatacatgtc agaatacctc ctggtttctt 105540 cagcatatca gaagcataca aaaggacctt ctcaatccag agaccaagaa tatgatatca 105600 gaacctatag aaaaggattc tgaaaatacg agaaccactt atttgattga agagatttac 105660 ttcggaaaat atttcaagaa gttacttgtc ccaaaattct catagatgtg taagtacacc 105720 gaagttagaa gtcatatagg caataaaagc atccaagctc tatttccatc atctactctg 105780 attaaaaggc tcaactctcc tatcaaattt gagataatca tgtggattat gcagcacagt 105840 gacttgctac atgttcaatg ctcaaaaaga tgataggtgt tattagccac atcctacggg 105900 ctgcgtacat acttattagt ttatatatat acataaactg atcctaaaaa attcttccta 105960 catttctgca agagaattaa aaaggcagaa acaaacattt tgcataaatt tactagcttc 106020 attctttcat gtaggaaata gttactgact accttctgta tgccaggcac tgtcattagg 106080 cttccattct agtggtgaag caaaacaaca aagaaatcaa tatgcaagac gtcaaatgac 106140 attaaatccc acgaagaaaa atgcagcaag gtaaggggaa tgcagaagat tgaacctgat 106200 cattctttga tgcagctggt caggaaaagc atcatttgag cagagagctc tttctgaatc 106260 aagtgagcaa ggaagccaca tggattatca cagagaacgg tcgcagggtc actgacaata 106320 gttatgagac ttaagatgac aaggatacag tcactgtaga cagagataag caagtaaggt 106380 agagagatca cagaagtgaa aggaagccag ttcatacagg gccatgtaaa tctccagatt 106440 tcacttttaa gatgggaagc ctctgaaaag ttctgagcat aataaataac acggtttaac 106500 tcagatttta aaaatatcat tctggctgct actagagaat acactgtaaa gtgtaagact 106560 cctgggaaac aatttctttc ttttgccaaa atatgatgcc tttaaacagg gtaaacagaa 106620 gtataatggt taaaaaaaaa catgaggcat gggtattttg aaggtgtagc caacaagatt 106680 taccaataat ttgagtatgt gacatagaga aattaaaaga tgcttccaag gcttttggtt 106740 gcacaggagg gaaaaaaagt tgttactaac tgagacggca aaagatgatg agagacgtag 106800 gtttgggagg atgaaaatca ggagctccac ttaggacatg ttaagtttga gaatgagact 106860 taactgttgg ataaatgagt ctacagttca gagggcaaga gttggtgatg gaaataggag 106920 agttgtcaaa gcgtagatta aaagctctaa cctagagaga aagaataaaa acgtccccag 106980 gactgggtcc tggggcattt ctgacattta cagtaaactg aacatttatt aaaactaact 107040 tgctttactg aaccataaat cacttgctgt atttacccct gctccattta tagttataca 107100 cctgaaaaca tagccttagt gttagaggta aagagtaaat accaaacata aaaaatccaa 107160 tctggtaggg tgcggtggct cacgcctgta atcccagcgc tctggaaggc cgaggcaggc 107220 agatcacgag gtcaggagtt tgagaccagc ctggccaata cgggcaaact ccaaaaaaaa 107280 aaatctgaag ttactgagaa actgatatga aatcattaag aaaattaagg ggtctaaatt 107340 aatacataca acaaagagat cccacaacat ggtttttata aatttaaaca aaatccatgg 107400 ccaggcacgg tggctcacgt ctgtaatccc agcactttgt gaggccaagg caggaggatt 107460 actttggggc caagacttca agaccagcct gggcaacata gtgagaccct gtctctacag 107520 aaaaaaaaaa aaaaaaatta atgttttagc ctggcatggt ggcatgtgcc tgtagtccca 107580 gctactcagg aggctgaggc acgaggatca cttgagccca ggaattcaaa gttgtagtga 107640 gctctgatca caccactgca ctccagctct gtcacttatg acaaagcaag acactgtctc 107700 aaacaacaag caaacaaaac aaaaaactaa agtaaatcca ggtaaaataa acatacaaat 107760 aaatgaaaag gtctgggtta ttgcattagt tctgtttgta ggcttaacta caaaatggtg 107820 tccagttgtt aaaaatgttt gcttaggagt attgattttt tttattatgc tcttctacat 107880 tctaggaaat tggcaacatt aagaattcct aaaaacaaac aggagtgtta agtgtataaa 107940 aattattatt taagatgcat tcaaggcatt ccttagttaa attaaaatat caaatgcatg 108000 tcaaattaca cacaaaaaaa tcatgcttca acaaaagtgg gatgttgcca ttaatggaca 108060 gttagttctc aggtaaaacc aagaatcctt cattacctat tctgtaaatt aggacaaata 108120 ctattaaggt attaggttgg tacaaaagta attgaacaaa cccagaccta ctcacctcac 108180 tgaaagtgct gcctggctat agtctctaga tacaggaatg tgagaaatgg tagcagcctt 108240 gaaggtttag agctgtattc tcataccaat tatggctaga aacttaaaca gctctactga 108300 gacattatgg gaggtctaat ttcctgttac tctactttaa cacagccaag taaaacagta 108360 agaaagcttg cttaatttga caaggactga atgccagagt gtcacctgga aacttgtgac 108420 aaataatcat gcctcacaca ttcatccttg gtttttacta ccaaatgcaa gcttcatcta 108480 tcctcttcca ttctaaactt gactcatcct cctaacctct tccagaaaga tctctagaaa 108540 cccagagtct ttctgaagac ccacaggctg tcccctatct tcaactactt tacataatgg 108600 cccctcaact tcttagcttt cacgaaagcc tggctcttcc ctgaaggcac ggcctatcat 108660 gcaacccttt tatgtgactc ctaaaaccca agtccaccat tattcttcta atactctgta 108720 ttaaaaataa acaacaaaat tccctgtatt aaaagcaaac aacaacaaaa aacttgtaat 108780 ttgaaactca cgtcatttaa ctgaatgcct tctctttctc tctgttctgg tcaactcaac 108840 ccacatattt aagcctccac tttgccccca gttacatcat cagcaaagtg acttcaatgt 108900 ccctgtacat ggttctatcc caatactcta ggcccccaaa atatctgcct ttctaaattt 108960 gagatatctt cacctcctca tttcagcaaa tcactccctt gtctttgtta gacatattaa 109020 aacctctgat aatgatcatc tcagctatct ttataacagt ttcactcata ctcatatctc 109080 ctttcaccta tcaagacacc aggtttggtg acaaataaaa atgatacata tttgggaggc 109140 tgaggcagga gaatcatttg aacccaggag gcagagaatg cagtgagcca agatcatgca 109200 tgctactaca ctccagcctg ggcgacaaag caagactcca tctcaaaaaa aaaaaaaaaa 109260 aaaaaaagat acgtacttat tgtatacaca tgatattcca aaatatgtat acattgtgga 109320 atggctagat caagctaatt aatacatgca atacctcaca tacttacatt ttacggtaga 109380 acatttaaaa tttactctta gtgatttcca agaatacact gttactaact agtttccatg 109440 ttgtacaaca gataccttga acaaattcct cttaattgac caacatctct gcaacccagt 109500 ccatccaccc ccagcccctg gtaaccacca ttttacatct ctgagttaag attccacatt 109560 taagagagat gtagtatttg cctgcctttg tgtggctggc ttactttaca caatgccctc 109620 caggttcatc cctgctgtca cagatgacag catttcctcc ttttgatggc tgaagtgtat 109680 tccactgtgt atctatacca cattttcttt atccatgaac gcgtaggctg atgctgtatc 109740 atgggtattg caaacaacac tgaaaggaac acgggagtac agatctcttc agcacactga 109800 tttcattctt tgatacatat atatatccaa gtgtgactgc tgaatcatat ggtagttcta 109860 ttttttaatt tctaagcaaa cttcatgcta ctttccataa atgctgtact aatttacatt 109920 cctaccatgt gcaagatatc tccaaatcct catcatactt ttaacagcca ttctaatggc 109980 catttgaatg tcttattttg agaaatgtct attcaagtcc tttgtccatt tcttaactga 110040 ggtgcttact attgagattt ctgagttccc tatatatttt gcatattaat cccttaacag 110100 atatatggtt tgcagatact atcttccatt ctatgagttg ttttttcatt ccgtagattt 110160 tttctttttg ccatgcagaa gctttttagt ttgatgtgat ctcattcatc ttttattttt 110220 gttgcctgtg ctttggggtc atatccaaaa aaatcactgt ccacaccaat gtcatgtaca 110280 tttctcctat attctggtag ttctacagta acagctctta cttttaagac cttaatccat 110340 tttaacttga atttggtata tgatgtgaca tacaggtctg atttcattct cctgcatgta 110400 gatattccgt tttcccaaca tcacctattg aacagacttc cctttccctg ctgtgttctt 110460 tgcaccttgt ccaaaatcaa ctgacagtac gcgaatttat ttctgtgctc tccattctgt 110520 tctatgggtc gatgtgtctg tttgtttctt ttgttttgtt tttaaaagac agggtcttac 110580 tctgtcatcc aggctgcagc gcagtgatgc aatcacagtt cactgtaacc ttgagctcct 110640 gagctcaagc aatcctcctc cttcagcctc tcaggtagct aggattacag atacacagca 110700 ccatgcctgg cttaaaaaaa attttttttt tgtagagaca tggtctcact atgttgccca 110760 ggctgctctc aaactcctgg tttcaagtaa tccttctgcc ttagcctccc cgagtgctgg 110820 gatacatgtg tgagcaactg tgcccagcct gcgtgtctac ttctatgtga ctaccatgct 110880 gttgtaatta ctgtagcttt gtactatatt ttgaaatcag atagtgtgag gtctccagct 110940 ttgttctttt tactcatgat agctttggct atttaggatc ttacgtggtt ccatataaat 111000 tttggcactg ttttctagtt ctgtgaaatt taacattgga attttgataa ggattgcatt 111060 aaaactgtag attgctttgg ataatagaaa cattttacaa tattaattct tccaatccat 111120 aaacacaaga taactttgtt tatttgtatc ttcttctatt tctttaatca atgctacata 111180 gttttcaact atttggttaa agttatttct aagtacaatt atccctcggt atctgcagga 111240 tactggttcc aggatctccc atagatacca aaatccatgg atgctcaagt ccattatata 111300 aaatggtata ccatttgcat acaacctata cacatcctct tgtatgcttt aaatcattac 111360 tcagtaccta atacaacata aatgctacgt aaatagttgc tatactgtag ttttcttatt 111420 gtataagaaa acagtatttt ttattgttgt attttttttc tcaaacattt tcatccaaat 111480 gtggattcaa tttgcaaatg cagaaccacc gatactgggt gttttgtttt tggtacctat 111540 cataaatgga attgtcttct tgatttctct tttggataat ttgtgattaa tgtacagcaa 111600 ttctactgat ttttgtaact tgattttgta tctcacaact ttactgaatt tgtttatcag 111660 ttctgacagt tctctggtgg agtctttagg gttttctata tacaagatca tgtcatcttc 111720 aaacaggtgc aacaacatct tcctttccta ctgggatgcc ttttctttct cttgccgaac 111780 tgctctcaca aggacttcca gtactgtgtt gaacagaaat ggcaagagtg ggcattctcg 111840 ttttcttccc aatctcaaaa gaaaagcttt caacttttca acattcagta taatgctagc 111900 agtggatttg tcaatatggc ctctatttta tagaggtata ttccttctat atttaatttg 111960 tgagagtttt tagcacaaga gaaagctgaa ttctgtcaaa tgctttttct caattatctc 112020 aattatctat tgagatgatc atatggtttt ggcctttgtt ctcctaatgt ggtgtatcac 112080 atccttgtac ccttgcggta aatcccatgt gatcacagta aatcatcctt ttaatacact 112140 gttgaattta gttattattt tcttcagaat ttctgcatct aaattaagaa tacaggtctg 112200 taattttctt atcctggaga gttgtttggc tttggtatcc aggtaatgtt catctcccaa 112260 aatgagtttg aaagtattcc cccttcttaa atttctcata aaattttgag aacaatttgt 112320 actagttctt ctttaaatgt ctgctagaat tcagcagtaa agtcaccaag tcttgggctt 112380 cctttggtgg gaagtttata caggaaggat tatataggaa ggattataac tgatacaatc 112440 cttgtcactg ttcaaatttt taatttcatg attaagcctg ggcaagttgc atgtgtctag 112500 gaaattatcc gtttcttcta tggtaatcag tttgttggca tataattgtc ccgtctctta 112560 tgatcctttt atttcttgta cttctctggt atcagctgca atgggtcctc tttcatttct 112620 gatttaactt gagtcatctc tttttttctt agtctagcta aagacttgtt gcttttatca 112680 tcaaaaaaca taactcttaa tttttttgat cgagttacct ttttccttag tctagccaaa 112740 taacctgtct tttaagttca gattcttttg tctgtttgct caattctgct tttaatgctc 112800 ttttgcattt ttcattcaat ttattgcatt ttcagcttca gaatttgttt tttacaaaat 112860 aatttcaatc ttgaaatttc tcattttgat tgttttcctg attttgttta attgtttatc 112920 tgcattttct tgaaattcat tgatcttcct taaacaacta ccttgaattc tttgtcaggc 112980 agttcatata tctccattta tttacgggtg gttcaggcgc cttattgtgt tcctttgact 113040 ggtgtcacat ttccctgact gttcttgatc cttatagtca tgtgttggca cctgcacatt 113100 tgaagaagct gagacttgtt ccagtctttg cagagtgacg ttatcgggga aagtccttca 113160 ccagtcggcc tgtccagaga tcatgcagcc tgagtccaca ggggctggcc tggcatcctg 113220 gtctactaga gtgagcctga accttgggtc tgcaaggacc agtgtgaagg ctgggtaggt 113280 gggtgttggc ctagaatttg gatcacaagg ggctggccaa gtactgggtc tgaacccttg 113340 ttctgcaggg atgtgaggcc acaggggccg atctagaggg cagggctaca gtgaccagcc 113400 tagcactaga caggcttgga gtctagggct atgggatcca gcgtggtgcc ggggtgggcc 113460 tgtaggcttg gtttgtgggt attggcctga agtctgggac catgggggcc cgcctagcac 113520 tgagttttac tagggcaagc tcaacgttag ggtctaagtc tggtgtacac ttcccctcct 113580 tcaggtcgac agtatctctc tccatgatgg gctgtcaggg attgagggag gtgtgatgca 113640 agtaatgtaa aactgtcctt cttacccttt tcaatgtatc ttttcttatt tgtgtggcac 113700 attcaggtaa tctctcatct gatttcttag ctcttatatt tttgtgtgtg gatagttgtt 113760 caaattgatg gttccacaat gagatgagtg ctgcaaaatg ccagtctgcc atcttgctgt 113820 tatcgagacc tcaggctttt cttaaaacaa ctcaacactt tggtcgtgca tcccaacctt 113880 tccaatcatg gccatcatca acagcatatg aattcaaata ctccaatgtt aacatcttat 113940 gcacatgcca ctagtgattc tgtttcatca gctctgctaa tatccaaccc taaaatacca 114000 tgcataatct tctggctatt ggagaaaagt cttgaaattt caagtgtgat aaggtcttta 114060 atcttaacta gccactcagt ggaatgagat tctcctaatc tgatatggtt tctggtttca 114120 ggtagccagc caagattctc aataactttt gatcaacttc ttcacccatt cccctcagta 114180 gcttcctaag ttttcagtct tctcaaaact tctaaacaaa ccctttattc cacaaaatat 114240 tattaaaaaa tatttcataa agtttcgtgg tcactaacct acagtaagat actaccttac 114300 acccactaga atgactacta ttaaagtaca cacacacaca cacaaatatg tgatgggaag 114360 gatgtcgaga aactggaccc cttgtacact agtggtagaa atgcaaagct acaattgctc 114420 tggaaaagag tatggcagtt tcttaaaatt ttaaaaataa aattaccata tgatccaaca 114480 attccacttc tgggtatgta tgcaaaacaa ttcaaagcag ggtctcaaaa agatatttgt 114540 acactcctgt tcatagcaac attatctgta atagctaaaa catggaagaa acctgagtgc 114600 tcatcagcag gtaaacggat aagcaaaatg tgatatatac atacaataaa acattattca 114660 gcctgaaaaa ggaagcaaat tttgaaacac gctaaacata gatgaaacgt aaggacactg 114720 cgaagtaaaa taagtcaatc ataaaagggc aaaaactgta tgatttgcac aaaaactgta 114780 tgatggtact tagagcagtc aaaattagac acaaagtaga ataatggttg tcagaggctg 114840 tgaagataag gaaatgagga attattgttt aaagggtaca gagtttcagt tctgcaaaat 114900 agagagttct gacggtgact gtgcaacaat attaatatac ttaataccac tgagccaaat 114960 acttaaaaat ggtgaaatgg aaaattttac attatgtgta ttttacaaca attttttaaa 115020 acttaaatga caagtcacat ggctgagtca cataaatttg agaaatacat tttatagtca 115080 tttcttgcat attcacaaca tacaccagca tttaaatagg gttacaatat tttcagtaag 115140 aatatcttga tttttccaac ctcacccaca attacaatta atatcacaca tccaccttaa 115200 cttccttctt ctaatttcat tagatgggca tctttcctct tattcaaggt caatcactat 115260 atctgcattt ttctttcttt tatattacct gtatgagaga tacacctgta cttttcattc 115320 caatccttac taccttgaaa aactttgctt tgataattac tacctctatt atctgaaaca 115380 tctttagtct ttacaataaa ttcactagtc ttacttactt catgttctaa atatttttta 115440 aatccagaaa aatttatctt gaattcctat tataccactg tcattgttaa ggttctcact 115500 gactgaacta ccttaccacc acacgtttct cttcaatcct ttctctgctg caaggttatt 115560 aaaaatacac gtttgacaaa cttactacta tctacctact gagcaatttc tttgctgact 115620 cccaaatacc tttctatcac atcttatctt cttcattttc ctacctctca gctagcttat 115680 gatctacaag tcctcaactg cctattgccc ctactgccta tgctgcttct gaactttggc 115740 tcatacttct gcctagaata agctggtcat gcctctacct gcctgattcc cagtcacatt 115800 tcaagactga actaagcatt tcctggccac tcttacttcc ctgccatcta tactggattc 115860 ctactgcaag cctgggtact cactccagta ctcctttacg ttactattgt attctggata 115920 ccattccacc tcaacgactg aaattatttg cttctgcatc tttcactctg agtataatat 115980 aaatttctgt agggtgaaaa ctaattattg tgcatctctg tatctataac gtagtactga 116040 tgccttaaac atggtagccg ttgagattgt taaacttaac tctttcctca attcccctat 116100 ttccttacaa ctgctaccag ggaagcaaaa agactaagaa ttcaggcgtg tgcaattatc 116160 tatctagtag tagaaatcca gtaaactgtt accaaggttt agagttatct ggtaggaaga 116220 aaagtaggta tgttcctatg tcccaattta ctgctaaagg attcctttag tttaaccaga 116280 aattatttcc aaataatgtg acataattta aagcagtcta gggcaactca aaataagata 116340 tcacagtctc aaccaagtta cacttacatt cggctagctt caatgtcgtc agactgaggt 116400 tctcctgatc tgtaaaatgc aattgagaaa cagttagcaa aatattccat actccaaaaa 116460 aaggtagaca tattacttag gaagacaaat ttgtaaacaa gatttcagca ctaaataaaa 116520 cagttttaaa aatacagacg taaacatgaa agaaagtggt cagatcaagt ggccatacaa 116580 cacatttatt ttaatggttg gactatcaaa aaactcaatg catgtttttt aaaggaaact 116640 gtaaacgcta tacatagata ccaacagaca agccattata agccataatt attcacaaag 116700 tcaaatacat gtaataaaac acacaactat aaaacttcct atagccaagt attggttatc 116760 cacattaaca aaggtactca ctggtattca cttgcagtat taacctttag attagtgggt 116820 cagtaaacta ctccctaggc agaccgacta aagcctaggc cagccatgta gttttgtaaa 116880 cgaagtttta ttggcatgca gccatactca ttcatttagg tatcatctat ggctgctttc 116940 acgctaaaag gacagagctg agaactcgtg gcagaaacca catggcccac aaaacctaaa 117000 atatttattt tctggccctt aagaacaaat gtgccaaccg ctaccgctac tctagacaat 117060 gcaaactaaa atccagtacc ctggtaagtt taaagacact taaattagat acaacatcca 117120 aatgatgatt atcttggttc aaaaatgaaa ttgtttccct aaaaatacac ttactgtatg 117180 tattacctgt caaaagtgta ttacctgagg taaagttttg cactggatag ctgtgaatta 117240 acttccgttt taaatagttg ccagttactt tgttatttct aaatatacca ctgctctctt 117300 atgtagaaat atttaaaatt ctaagtcact aaaaagcctt tcattttcat ttcacgagac 117360 atgaatcagt atttccctat ctctaccatg tcgttaaaaa taagttcctg ttaccctatt 117420 cacttttata aacagcatca gcaacaatga atgatgtaag gcgagtcaat ataatacgga 117480 tttctaacac ttagaaattc ccaaactaga taaaatatgt tttttgaggt caaaagctaa 117540 attttctaat tggcattaca aagtcctgat ttgtgaactt ctcactgact ttaggcttcc 117600 aactttaagc aactctaaca agaatcaaaa tcagagtctc acacacacac tctctctctc 117660 tctctcacac acacacacac acctgtttga taaatgtctt agcttaaaaa caaaaaaaca 117720 aaaaaaaact tcacttcttt atcagactct caaaattacc ctcactgcaa ttcattcaga 117780 ttccaaggac aagaatggaa aagaaaaaaa aaaagactcc agcagctcaa atatttattt 117840 tagatcttct ttgcaatgta tttaaatttt caattttgca caaaattacg taagaactaa 117900 aaactggggc atgctggagg tggcagtgac ttggcagtga cacaaatgca aaaatttcac 117960 tccaccctct cccccaggga gcaagcaaac cacctatgtg acacacctgg tctccaccag 118020 cctgtgggta agtaccccaa gattgcttcc aaacttgtat ctcccagaca gaagagctaa 118080 aaattgatga taaccccatg taccagctga ctcatttttg aaagtgcgac cctccagcat 118140 cagatgtcat actgtaagga ggcagagctg gcttgcaaaa caaaaaataa acctgctggc 118200 actgagggaa gagaggcaga ttagaagctt tcaaacacgt aggcagcaaa actttcaaaa 118260 ttaacaggga aagagaagag aggggaaaaa atgaggacat gatgatagga aaataaaaat 118320 attactgcaa aaaggtaaga cacaagaagg aaaacaaatc taagtcttag aagtacaata 118380 tgtaactgtt acaaagtttt gagatcctgc aatgggatag aatttaaata cattatcaaa 118440 tgataactat atctgtcttc ccaatttctg tttcctaagc aagagaatat gtgaactttg 118500 gcatcaaaat gtcaccaaac tgtaacatat taattactac tttttacata tattaaagta 118560 ggctattaaa aaccactgat aagacaaact aagtaaacca attcagtata gaagaaggac 118620 aaggactgaa agattattac cttaaaataa atctgtcctg gatctattaa acatagcaaa 118680 gttgttctat tcaaattgca aattgttttt taatcaagag aaaaatgaat atatacagaa 118740 ctagcagaca tttttcttgc agtgaatatt aataatttat gtctgaataa atttctactc 118800 atcctaataa cagtatattt ctagaatagt ctaaataagt taccaaaaaa atcccaagtt 118860 tagaattcaa actctcaaaa ctatgaaata cgccaggtgt ggtggttcat gtctgtaatc 118920 tcagcacttt gggaggtcaa ggcataagga tcacttgagc tcaggagttc aagattagcc 118980 tgggcaacat gatgaaacct cgtctcttag ccgggtgtgg tggtgggcgc ctttagtccc 119040 agctacttgg aaggctgagg tgggagggtc acttgagccc aggaggtcaa agctgcagtg 119100 agctgtgatc gtgccactgc actccagcat gggcaacgga gtgagacctt gtcttggaaa 119160 caaacaaaca taaactatga aatatatacc acctagtaat agttcccaag cttgactgtg 119220 gctcctaaag agtttactta ttcttttact gccaagttgc tggaaataag aatcctgtat 119280 gtgcttgtaa atgcagaaca tataatctaa ttcaaaacat ataaccaaag ggaaattttt 119340 gtattaaact attgacttag gttatcctaa agtgtgtcag aataacaagt cagaaaagaa 119400 attttaaaac tgaaacaata accaagtaac attagataat aaaaagtaaa tcttagaaga 119460 gtctcaattt taggtcttga tttgaatcgc agaaaatatg atcacaaaac gcccactaat 119520 ctgaatactg cagcatgagc tagcaaattc aaatggtggc tcacttccaa taacactggt 119580 gcagcttctc catcctgcaa gccactcctt ttacctccac tgtaactctc taggagagaa 119640 aagtatacta gttttattaa tgtcataaaa acttctagag aaatgtttag ttaaaacgtt 119700 caccacataa aaggcatact ttaaaataca tattaagaaa tttttcatgt tttctataag 119760 gtttatagta aaatgtttaa aactttgaag gtttttgaga aatactttcc tgttcataca 119820 gacaggtctt tgatagtggc tactgatatt tttaatagaa aaaagacact aaaatatttt 119880 aaggagatta aatgaagcag gtcaactctc aggcccacta ttcttagcaa tattcctgcc 119940 aactatacat tgtcttcatt tctacagtat gtatttcact ttacaatgac agccttttaa 120000 aggctgtaaa ataattcaaa attacctttt acaagctgtg gccattcggt gacatcaggg 120060 tgatcacagc tttgagtcac tgattaaaaa caggttgtca caccagtcta gttgctacct 120120 tgatctgagc gtaggcttaa taactctaat aaattaaaca aacctttggt tagaacactt 120180 taatatataa acccaattca ttgttcaaaa aataattttc aaagcttcaa attaggtgtc 120240 aatgtaaaat tcatcagaag agtaattatt atagaaaagt ttttaaggac tattttccag 120300 cattttgttt ttcttaaatg atctcttcat ttgagaaaat gtaataattc cttgtacttt 120360 tatgtaattt tacactttat gaagcatttt ggtcaataat accttgagtc ttgtaacttt 120420 tgctttacct gatcgagaca gataatatag taagaatttt ttaaaacaaa caaaaaaaaa 120480 ttaagcagcc tccgagtgat taactgactt gcccaagatt ttggaactag tgttgaagga 120540 atgattaaaa cccagatata ctgacttcct atcaagggat ggattttttc gtttgtttgt 120600 tttggcttag ttttgctata ctgggtttca agatttaagt atacgtaatg agtaaagatt 120660 cacaacatag attgagatct ttcaaatatg gcaagtttaa gtggggacta atttactcaa 120720 aagattctta agctgataga gaaatcagtc accaagtagt caaatgctta atggaatagt 120780 tatatatata cacataaaca cacacacaca taaacacaaa gtctagtcct actaactcta 120840 tatttacgta gagtcattta acatcagtca aaaccccttc agtactgcat gaaaatatgt 120900 tctactcttt cttggccata aacctactaa gatttaattt catgaaaaag tatggcaaaa 120960 gatgaaagca tatcctcctc cctcaaccaa gtatcttttt aaccccttac atggccttag 121020 ctgaactttt ctgattgtca cagttcaaat ttagcaggcc tctttactca cactgtagtt 121080 ctggcaaaga taccacacat ctgaaatatt ccagtatcaa atgatcattt tgtacaacta 121140 gttctttccc ctcacgattc ccctatccag gccaaatctg aggtgtcaac tacagaaagg 121200 tgaggaaatt aggaggaaga aacatttcgt agttaacatc ctcaaagcaa caacagtcaa 121260 gcgcagaagg tggttaccag tgtggattca gaacccaaca taaaacagca aggtatctgc 121320 aaataccaag ggttaaataa aacatgaatg tctgagccca tacctatgca gttatgaatg 121380 cagggcttca aaatccagat taggtgagga ctggcctgaa tatacaaaaa taattgtagg 121440 ggattccaat aaatggaatt tacagtatct gtaagaaata acacaatctc ccagatattc 121500 ctatcctaag catacatttc ctaataagaa cctagacatt gctgaggtca tatgggaaac 121560 accaccttcc ctaaaataaa caatgtggtc atgatacagc tttcccttgt gttctcaaga 121620 ggctaatggt atgtggaatt agaagattca aacaagtcta actttctatc ttgtaaacac 121680 aaaaataata aagttaaaat accttttaat tgactaattg atctcaatgt aatgaaaaga 121740 gctatatgta ttttgaaaac tactgagtca agtcctctct tccagtcccc tcttttatga 121800 gataccgtgc tcaaaaggct ccaaggccag gctggattta cgtctgtttg gtcactcact 121860 agctgagaaa tcttgggcaa gttacttaat ctctccgagt ctcagtttcc ttagacgtag 121920 aattagggta atagtaccta ttccagagag ctgtcatgga tgcacaagct aacacctaaa 121980 tatctcagaa cagtgcctga catataatgt gctcacaaat ggtcgggtat ggtggctaac 122040 acctgtaatc ccagcacttt gggaggccga ggcgggtgaa tcacttgagg ccaggagttc 122100 gagaccagcc tggccaacac ggtgaaaccc cattcctatt aaaaatacaa aaattagtca 122160 ggtgtggtgg cacgcacctg taatcccaac tacccggcag gccgaggcat gagaatcact 122220 tgagcccggg agatggaggt tgtagtgagc cgagaaggtg ccactgcact ccagcctggg 122280 caacagagca agactctgtc tcaaaaacaa cagcagcagc aacaacaaca acaaacggac 122340 aagctattaa tactcatagc ctaaaatcca aacctgccct ctcaatcttt ttatgcgtat 122400 tattttacct tcatagcaat tgtaaatgtt ttcagcaccc tacctgggtc cctcatacag 122460 tcttggaagt gtagttagtg agcacctgac acaatgcttt aaaaatggca ggggcccaaa 122520 tttgctgaac atatctgtca ttattatgac attaagatac acatgcaata cgaattccaa 122580 aaaataaaac aaaaacatac catatttcgc caaacttctg aggagctggt gaattctaaa 122640 atcaggctct tacagatttt taacctaaaa tataaaacac ctcactcaat tctttttata 122700 taaacaactg gataaacttt caaaaaaaaa aaaaagaggt actaaatttc atcatgaaag 122760 caaatttatt ttctataata attatgaaca tccaaaaacg tatcaagaaa caaattactc 122820 tatagaggct gccaggatga ggaaagcata ggtaggcagc cctgtggcct gagtgctttc 122880 agcaggcaaa gccgtatttc ccatattcat tcacaaagct tactgccttc tatttcttta 122940 ctctatcctc cctccaaaag ggctaaatac ataggaaaac tatttgacta tatcccccta 123000 atcccttcaa atacctatag caattttgtt tttaattcta tatgctaagc atcggctatg 123060 ttaggtacaa atctgggcat ctacctacca ctttccagag tagcagcctt gggtcgaccc 123120 tctgaccctt gagtctccaa tgtcaggtta tagtagtaga gaagatgcat taaaaaagca 123180 tagtataatg cctacctggc acaaaacagg acttcaatat actacgataa ttacaattta 123240 ttaaatcaac cacttaatat atatcaaaac ttaactctta aaaaaaaaaa aaaaaaaaaa 123300 atcctgacgc ttacagcaag cccctaaagt atcgctgtaa attcttaact tgtttgtata 123360 caatcagaac gttcctcaat ggaacagaaa taaagtcctt taatgtactg cattacatat 123420 aaagaaacca aatctcaaag attaagaaac ctatccagtg tcctagaggt tgattgcaga 123480 aaatgaatac actgcatatc aacattttga aataaaatta accaactttt aaggttttag 123540 agactgagtt tcaaacttca gcctataaca aaattacctg gggaaatcta aaaatgcaac 123600 tactcgggct ctacccgcaa agattctcat tcaatgcatg aagtaggggt tcatgaatta 123660 ttttttttta tttttttcag acccatccaa gaacacagaa atgaatttgc attttaacat 123720 atacttcaca tgacacacag atctcatttg aagaagccct cccttccaaa ttacgagtta 123780 ggaacacata atcatagagg aaatacacca aatctataaa aatacagaat aacaaaaact 123840 gtaagcatta caaatattag gcacactcac ttgccaattt aaccataaga atcctaatac 123900 cagacatagt tctcttactt tatctcttca acagagggct cagtctaata attttataaa 123960 taagtatagt ctaataagac atacctatgt tgatctacat ctgtctccct aaaattttca 124020 ttttattcat ttctatttct ccttcacctc cttctaaagc tgtttcaaaa cttaatttca 124080 caaactgttt ttttttctat cactttttat cataacatcc aacacttctg ttctcctttg 124140 caccatgttt atggtgtctt atatttatgg ataatgctac ttattaaaac tgtctacgtt 124200 tcatccgttt acacatttca caactaaagg actactccaa caattttcct aagtcttcct 124260 gctttaggct ctcctcattt cagtccattc tgcagttaag acttaaaaag ttttaaatac 124320 tgctttcaaa taatacttgc aacataattc cctcaactcc attagctcct cagagtacca 124380 tttctttatc ctctttcctt tcactgccaa aaagacgtga aaaccactag ctcagctgct 124440 gttttcctac ctactgaaat ttttcttaca aaagtttcca tcatttctgt atattctccc 124500 agtgctttgg ccccttaatt ctacttaatt tttgtagctt ttaagactgc taatgactcc 124560 tcatctcctc tggcttccct catgtaggat ccactcattt ccttccatcc ctctaaaggc 124620 aacaaggtcg tctgctagtt catcttccta cctctcatac atggcctctc tccaagtttc 124680 ggtcaatagc catttttctt aacctaaacc aattttctgc gcaatgtcat ccattcccat 124740 agcacctcta tgcttacgaa cccctaactc tgtatcttta agcccttatc tctggcatgg 124800 tatgcctgta actacatatt accaacggta cacatccata tggatgtcta attagcatct 124860 acattcaacg tatctaaaat caaactcaaa ttattttccc aaagaactca ctctgcctaa 124920 tctcactgtc ctagttatga attgaaaaat ttggccgggc gcggtggctc acgcctgtaa 124980 tcccagcact ttgggaggcc gaggcgggcg gatcacaagg tcaggagatc gagaccacgg 125040 tgaaaccccg tctctactaa aaatacaaaa aattagccgg gcgcggttgt gggcgcctgt 125100 agtcccagct actcgggagg ctgaggcagg agaatggcgt gaacccggga ggcggagctt 125160 gcagtgagcc gagatcgcgc cactgcactc cagcctgggc gacagagcga gactccgtct 125220 caaaaaaaaa aaaaaaaaaa aaagaaaaat ttggtgccat tcattacttt ctccccctca 125280 tttttatttg ccctgaccac tgtgtaggtt gatactcatt cagccttcaa attcttcata 125340 atcattaatt cgaaaattgt ctactagatt ttgagtgcct actaggtgga tgaagatgca 125400 gtggtagaaa aatgagacat aatttcttgt cctcatgtgg tgaaggaaat gggcacaaat 125460 aaaaaccaca atgaattatg taattgcaat gcacagttaa gggttgtgat ggagaaatac 125520 aaggggtaag ttgtgtatta taataaaaag tccttagtct gaagaaaagg aaaaccattc 125580 tttatgaggg acaagcaaca tttataagac acactaagaa aaatcctgtg aggtaatgat 125640 ggtagcacta tcagtccagc tgctcaaatt ggaagattct cagtcatatt ctaaagagtc 125700 tctctctttc ccagtatatc caattgttta ccaattacta ctaattcacc cttagaaatt 125760 cccctacatt tctacattcc cacactattc cccggtcttt tttgatggct tttagttgct 125820 tccagaataa agccaaagct cccaatcatg tcagatgaga ctctacacaa tttggtcaaa 125880 acctgccagt gcagcctctt cttccagact agaccagact tcaagagaat atgtgtatca 125940 tttgctttta tacttccagt gcttgtaaat gttcatagaa taagcatctt acaaaagaca 126000 aattttttct ctttggggac ttgttttcag tcctttaaat gcaatgcagg ttaagattta 126060 aactctaatt tgtctaattc taaagaccac gttcatcatt cccttgtacc tgccttctaa 126120 tttatactca aaccctatac atttccttaa aaatatatct tactcctttt ttccccaaac 126180 ttaccaatac tgtcctactg gtttcccttt tgcctttatc ctcaattttc ccactagcat 126240 tatcttccta aaaactcaaa gttatacata tcgttctata ttcaaaagct ttaacacttt 126300 ctcatgccaa ccgaataaat ttctaactcc ttcacatttt atatgaggcc cctgcctgac 126360 cccagccatc ccagcactac tgcccactac atgacatcat caccaggtac cagatctagc 126420 cccatcattt gaccactggc tataatacac tggatatctg tgtttctgac ttcaatgtgt 126480 tcgcttctga ggagacttca ctcagaaatg gttctctatc cattactaac ctctatcccc 126540 cacccaccta tcatgccatg ttaaaaactg ccctcattct aaacactgta tctcacaggg 126600 ttgtctaaac tcttatacat aatcaccgtc tccttcatgt cttattatac attcttaata 126660 ccataaaata attaatgtct ccttatattt attatgttat accttacatt acagctatct 126720 gtatacattt gtcagtgcct ctagttgtaa gctgattgat gtagggatca tctcttccat 126780 attttaattt tcataataat ggtgactatg ttttcttgac accatacctc ccctctacaa 126840 ggaaaaaaaa aaaaaaagga atcaggaccc atggcctttg agctagttcc aaacgtgact 126900 catagatgaa caaaggtatc atttcttccc aaagcaacac aaatataagt aaatgccaat 126960 ttaagaaaca ttttatttca aggactaaat atgtaagaat aaccaaaaca actgtttcta 127020 ataatgtccc tttctctacc agacattaaa acatattaac ttaaatggta taattaaaat 127080 tagcacaaca ccttcaaaaa tggagtatac actaaatata tgcatacccc ctgacttaaa 127140 aatttccctc ttaagtatac atcaaaaaaa ttaagtacac atattcacga gaagacaatc 127200 actgaaatgt ttagagcagc agcaagattc ttaacaattc caaaccaaaa atgattaaat 127260 gtccatcaac agcagattaa actgtggcat attcttaaaa tggaatacta tacagcgact 127320 atcataaaca attactacaa ccaacagtgt ggataaatct cacaaacaca ttaaaagcaa 127380 tcagacacaa gtaagtgtgc ttgattctag ttaaaggacg aaaacaggca aatctaatct 127440 atgctatgag aagtcaggac agcggttaca catggaagaa aacggagggt aacagagcac 127500 aagcgagcac acaggagcga gcacacagga gcgagcacac aggagctgcc gatgttgctt 127560 cttgatctga acgctagcta aatacgtgtg ctcagtgtgc gaaagtgcag caagctatac 127620 atttggaagt gcactcttct gtatatttaa aagattttta aaaaaaatct gatatggtat 127680 tagcattaga caaagaggta aacacaacag aaagctaatt tcagagaaag atccaaaagt 127740 atctgacagt tgctccttct caaacaagaa ttttcagacc ttggataaca ggcagcacag 127800 gactgtaata catgaaagga caaaaacaaa ggaggtgagc catccactgc ttggatgcct 127860 gcctggaggt aatttccaac ctgcagtcaa tggaggggaa cccaacgaga agacagcagt 127920 ttcagtgagg tcagaatcaa gagatcagag ctgaggaagc cgaagtgggt aaaatgtatg 127980 acaagtgcca gacaagaggg gtgcttgtct gagaaggcag agaaatggct tcagaaatct 128040 gtcatgtgag agtctactgc tgagtactaa ctgtacacga ttaaggtaag tggaagctag 128100 ggaaagaggg gcagtgagct gaaatattcc cagtgcttat aaaggaccgg gagactccta 128160 aaattccctc taacctgagc gaagagaaca cggtgacact gggagccttc tctagacaaa 128220 ctccaatgta gccctgaagg aataaaactg accagcaagt tatttagctg gctacaaaac 128280 aaaacactct aaaagaaaac aaaatctagt cacccaacaa caaaatatta caatgtccag 128340 catccaatct tataaaatca ttaaatatgt aaaaataaaa ataaaaataa actaggaaaa 128400 tacaacccat aatcaagaga aaaaaccaac aaattcagag tgaaaaaaat catgaaatca 128460 ataggtaacc tgattttcag ttattacaaa tatgctcaag atttcaaaaa aatacatgaa 128520 gatgaaaatg aatcaaaatg gaatttcttg aaatataaag caaaatatct gaaattattt 128580 aacaaggcag gagaaaaaac agcaaaatag aagacaaagc aaactgaagc acaggcaaat 128640 aaaaaaactg aaaaataatg aatatgacgt taatgacctg tggataatac caaacagtct 128700 aacacatgtg taagtggagt cccagaaaac gaggaaatga tgaaagagga gaggtggtaa 128760 aaaatacata tatatatata tatatatata tatatatata tatagaagaa acaatggcaa 128820 caatcttcca aatttaagga aaaccataaa tatacagatt taaaaaaaac acaactctta 128880 gcatggtcat catcagaaac aaaaagggac aagaaaaaat cttaagagca gccagggaaa 128940 gaagacttag tatcaggaag aaaagataat tagcattatg catcacttaa cagcacggat 129000 acattctgag aaatgtatca ttaggtggca tcattaggtg attctgtcat tgtgcaaaca 129060 tcacagaatg tacttacaca aatctcgatt agatggtata gcttactaca gaactaggat 129120 atatggtata gcctgggtgc tcctaggtta taaacctgta cagcatgtta ctgtactgat 129180 actgtaagca actataacac agtgtaagta tgtatctaaa cctagaaaag gtacagtgaa 129240 aatatggtgg tataatctta aatgactatt gtcaactatg atctcttgtt gactgaaatg 129300 tcattatgtg gcacatgact gtataatcag acttctcatc aaaaacaaac gctgaaagaa 129360 aaacacatca actatttaac caagagaaaa gaaacatata tgtccacaca gagactgttt 129420 tcacacaaat gttcattgta cctttattta taatagctag gaactgaaaa cagcccaggt 129480 gtcccttaat agatgaagtc acaaaccact gaaacattca acagtatgga tgaatctcaa 129540 aaacattatg ctgagcaaaa agaaactttt tacaacacat aagtattgta tgactctgct 129600 tacataaagt tctaagcaag ttaaactaag atgaaacaat ctgaacaatg ttaggttcta 129660 cgggtggtgt ggggggaagg aataactgga aagaggtgca ggttctgtac cctgatagaa 129720 ctttctggca aaggtgtatg catttgtcac agctcatgaa atggtgtatg tggtcaactg 129780 tattttccaa agatggtcac aacagaagcc attctacatg ctcttaacaa tgtaacactg 129840 ttatcttttc atcaggtggt ggagtctatg gcccttctct ttgaatctga gcgaaattag 129900 tgactctttc aatccaaaga ctacagtcgt acctcaacta tctacagagg actggttcca 129960 ggactcccat ggatcccaaa atccaagaat gcttcgaatc ccttatataa aatggcatag 130020 tatttgcata tgacctacat gcatcttcaa atatgttaaa ccatctctag attacttata 130080 ataccaaata caatgtaaat gccatgtaaa cagttgttac aatgtattgc caaagacaag 130140 ctctccttgc caatccctga ccaaatgaga gattcatgag caaaataaat agttgctgat 130200 atgtaaggca ctaagtttgg ggcaatgtat tacacagcaa taaataactg gaacagcata 130260 gtaaattgta gttaaaaaca ctaaactact aagttttagt taatatacat gctgaagtta 130320 agggtgtggt atactaacat ctgcaactta ctttgaaaag cataaaaaaa gacagttgaa 130380 gacaggatgg atagatggac aacatagaag acaaaaacaa atataacaaa atgttagttg 130440 tgaaattata ttctacaatt attttaaagt ctctgtggct tgaaaaattg tacaataaaa 130500 tgttgaagag tgaaataaag acatttccat acaaataaaa gctgaaagat tttgtagcca 130560 gtagacctac actttagaaa tgtttaagaa attttttcaa gtagaaggaa aataacacca 130620 agaaacttgg atctacaaaa agaaatctcc acaaaggaaa agaaataaaa atggtaaata 130680 agagggtaaa tagaaaggaa tgttattctt agtttttaag gttctttgta agacaactgg 130740 cttttgaaag aaatagtttc aaatgctact gtggaatcta taacacatat agaagtaaaa 130800 tgttaagctc acaataccaa aacgaatgag ggagagtaaa tggatgtata ctattctaaa 130860 gttcttacat tatacattaa gaggaataat atttctgaag gcagactgcg gtaagttaaa 130920 ggtgcatatt gttaatccta gaagtgtcac tgggggaaaa aacagaggga caagctaata 130980 atggagacaa aacaaaattc caaaaatgct ccattaaacg aaaagaaggc agaaaaggaa 131040 gaaaagatga gacaaataga aaacaaacag tgtcttaaac acaatacagc caactgcaat 131100 aaatgtaaac ggacttaaac aaattaaaaa gcaaagatcg taaaaaatca atctgtaagc 131160 aagatgcaac tatacgctat ctaaaagaaa gacattaaat gaccaataag ttgaaaataa 131220 aaacacagca aaatgataca atgtgcaaaa attaatcata agaaaggaat ggatacacta 131280 ataccaaagt agactttaga tagggaacat taccggcgat aaacagagac atttcataat 131340 gataaagaca tcaattaatc aaggagacct aacagtccta aatgtgaaca cacctaatga 131400 cacagctttc aagattttgc ttcaaagcat atgaagcaaa aatgaacaga acagaaggaa 131460 gataaactca aaattacagt tgaagatttc aacattcctc tcttgataat tagtaagtgg 131520 acagaaaatt agtaaagata aagaagaaat acatgtatct atctgacaaa gaacacacgt 131580 tctgaaaaga atgtgaaaat atttgaacag acacacaaag aagaaaactt ctcaatggca 131640 gtcatgaaga aaatgtaaat taaaaccatg actttttaca cccattagaa tggcaattat 131700 tttaaataaa aaaacagaaa ctaccggcca ggtggtggct catgcctgta atcccagcac 131760 tttgggaggc cgaggcgggt gcatttgagg tcaggagatc gagaccatcc tggctaacat 131820 ggtgaaacct cgtctctatt acaaaaatac aaaaaaatta gccaggcatg gcagtgggcg 131880 cctgtagtcc cagctacttg ggaggctgag gcaggagaat ggcatgaagc caggaggcgg 131940 agcttgcagt gagctgagat cgcgctgctg cactccagcc tggcagacac agagaggcta 132000 cgtctcaaaa aaaaaaaaaa aaaaaaaaag gcagaaacta ccaagtgtta gaaaagaggt 132060 agaggatgta gagaaactgg aacccttatt cactgctggt gggaatgtaa aatggtgcag 132120 tcactgtgga aagcagtacg gcagtctcta aaaaaactac acatacaatt accatatggc 132180 ccagcaattc cactcctaag tacataacca aaagaattaa aagaagggac tcaaacaggt 132240 atttatatac caatgttcat agcagcatca ttcgcatagt taaaaggtac aaacagccca 132300 aatgtccact gacaaataaa tttaaaaaaa aaaaaaaagt gatatatgca tacaatgaaa 132360 tattgctcaa ccttaaagaa tcaaatttgg atacatgcta caatatgaat gaactttcag 132420 gactgatatc gtttgaatat ttgtcctgta cagatctcat gctaaaaata caatccccaa 132480 tgttgggggt ggggtctggt gggaggcaac tgggtcacag gcgcaacccc tcatagcttg 132540 gtgctgttct tgggatagag agtgagttct catgagatgt ggttgttcaa aaagggtgtg 132600 ccacttcccc accctctctc tcttgctcct gctctcgcca tatgacatgg ctgctcctcc 132660 tctgccttcc accatgagtg aacgcaccat gagggctccc cagaagctga gcagatgatg 132720 gtgccatgct tgtacagcct gcagcaccag gagccaaata aacttctttt ctttttaaat 132780 tacccagtct cagatattcc tttaaggcaa cacaagaatg gcctaacaca aggacattat 132840 tactatgaaa tgaaatgtgc cagacacaaa aggacaaaaa tcgtatgatt ctacttatat 132900 gaagtacctg gaggagtcaa attcacataa aaagtagaat agtgattaca ggtggatggc 132960 gagagtaggc aatgaagagt tactgtttaa tggatagagt ttcagactga gaggatgaaa 133020 aagtttcaga gatggacagt ggtggtggtt gcacaataat gtgaatgtac tttatgtcac 133080 tgaactatac acttaaaaac agttaaaatg gtaaatttgg tatgtgtatt ttactaccat 133140 taaaaaaaac caaaacactg caatgggata ccactacaaa cctctcagaa tgtgtgcaat 133200 taaagactga gaacatcaaa tgctgacatt tggagaattg gaactctcat acactgctga 133260 tgggaatgta aagtagtata atcatccgga aaatagtttg gcagttcctt atacatttaa 133320 acataaactt cccatgtgac ccagtaattc caatttaagg tatttaccct agaaaaatga 133380 aaacatatgt tcacacaaag acatgcacac aaaacaatac ctttattcac aacagcctaa 133440 actgaaaaca atctaaatgt tcaccagaat atgaatgaac tgtggtacac tcatattgta 133500 tttaaaaata caaaacaaac aaacaaaaaa tctgtgataa acacaaattg gatgaatctc 133560 aaaaacatgc caagtgaaag aaaccagaca tggaagagta catgttactt gattccgtgg 133620 atatgcaatt ctagagcagg caaaactaat aaacagatca gtggttgcct ggggccaaga 133680 gagagaaatg actacagaca ggaaggaact ttttggaggt aattcaattg ttctaaagct 133740 tgactgtagt agcagtgata gtgtatatat ttatcaaaat caataaaact gtacagttaa 133800 aatgggtgca tttcattgtg tatcaattat acctcaataa acttgatgtt tttcaaagtt 133860 tatgagaacc taatacagaa gaaggtggca tcttcagtgg agacacgatg ccttacaaga 133920 cagtcagcta cccgagtgga agaaaataaa aggtagacat aattcccaaa ccatgtgaca 133980 aatgcaatcc ggatctaaac catatcatac catatccaaa attatgctga atgttcagat 134040 ctaactttat aaattaaagt caataaaatc ataaaagtac cagaagaaaa tacaagagat 134100 tggccaggta tagtagctca tgcttgtaat cccagcactt tgggaggctg atgtgggagg 134160 acagcttgag gccagcagtt caagaccagt ctgggcaaca cagtgagata cgttttctac 134220 aaaaaaacaa acaaaccaac caaagaaacc cgactagcta tagtggcaca ggcctgtaat 134280 cttacctact ggggaagcta aggcaggagg atcacttgag cccaggagtt tgaggttgca 134340 gggagctatg gttgctccag cctgggtgac agagtgacat cctatctcta aaaagttttt 134400 gtaatatata tatgagatca tatttatatc atctttgtta gcatgctgaa actcagaagc 134460 tataaaagat ggacagatct gcctacataa aaactttaaa atttcacatg actagatact 134520 ataaaattaa agataagtaa taagataata tttgcaaaat ataacaaaga attaaatgat 134580 aaataaagaa tgcttacaaa tttaaaaaag aaacaacaca atagaaatgg accaaaaaac 134640 cagacaattg cccaggctat ttataaagat ttaaacagat tttatatata cataaatcaa 134700 aacannnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn 134760 nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn 134820 nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn 134880 nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn 134940 nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn 135000 nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn 135060 nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn 135120 nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn ntcagctgct 135180 ctggtcaaaa aactttggca ttatctttta cttctccctt tatttcccac tttcatctgg 135240 tctactacca aatcctatgg actctatttc gacatatatc aagaattcaa ccacttctca 135300 ccaccctcac tttgaccact ctgtccgttt cagtcacctc ttaatctgta ctctaccaat 135360 tggtctgttt ctgcccttgt cccccttttc agtctactct caacacagca acgagagtga 135420 tcttgctaaa cctaagtcat actttttcac tactctgctc aaagacttcc aagagcttcc 135480 catctccttc aatggtaaaa atcaaacacc ttattatgat caaaatatct gtaccctcca 135540 ttatctgtct ctttatttcc catcatttac ttttctaaag ctacaatggc catacctcga 135600 gttcttcaaa cacatcaggc actctcactt tggggtttcc ctattcacta caccctttgg 135660 ctgaaatgct cttcccccaa atatccacat ggctagctct ctcatctcct tcagttcttc 135720 acccaagtta ccatttcagt gaagttttct ctacctaccc tatctaaaat ttcccattac 135780 cctttcacct acaaacactt cccttatttg ttttttctcc ttagcactat gtaacatata 135840 ttttacctat ctttatgatc tctcttttta gtattaaagt gccatgaaag caaaggattg 135900 agtgggtttt atacactgct gtctccacca gctcctagaa aaaaatgccc actacacagt 135960 aggaattcaa gaaatgttta ctaagtcaac cagatggatg tgtatgcagc caaccatttg 136020 aaagattctt ataacatagt taagagaaaa aaataagtta catgaaatac aagttttagt 136080 acacaaaaat ctgtacacaa ggaattaaca tgaaattttt taaaaataca atttgcaata 136140 ccatcaaaac ataaaattct tagaaataaa tttttaaagt aataaaagta gtacaagacc 136200 tgtatactga aaactacaaa acatgaaaga aattaaagaa caccttaata aatggaaaga 136260 tgtcccatgc tcatgaatga gaagacagta ttaaggtagc aaaacttccc aaatagacct 136320 acagattcaa cacaaatcca ggtcctatca aaatcccagt ttcatttctt gcaagctaac 136380 actaaaattc catggaaatt tgagaaaccc agagacccaa aacaattttg aaaaagagta 136440 agttagaata cccacatttc ctgatttcaa gacttactac aaagctacag taatcaagag 136500 tgtgtgttac caaaaaaaca gacatacata tcaatggact atataactca gagtccagaa 136560 ataaattatt agattttgtc aattaaattt tcacaatgac gccaagataa ttcagtgggg 136620 aaagaatact tttcaacaaa tggtgctggg acaactgaat tgccacttgt aaaagaatac 136680 aattggatct ccccctcaca ccttacgtaa aagttaactc agaacagata ctaggcctaa 136740 atataagaga tacaactgta aaactcttag acgagaacag gtataaatct ttacgatctt 136800 ggattaggca atggtttctt agataccacc accaaaagaa caagcaacaa aagaaaaaaa 136860 aaattgactt caccaaaatt agaaactgtg tgcttcaaag gaaaatgaaa agacaatcca 136920 taaaatgggg gaaattattt gaaaatcaca tatctgatga gggacttgta cccagaatat 136980 atttcaaaaa ctcgtacaag ccaacaataa caaaaattta aaatggcaaa agaaatagtt 137040 ctccgaagat ggccaatcag catatgaaat gacgttcatc accgtaagtt gtcaaggaaa 137100 tggacatcag agccacaaag atccttcaca cacacaagaa tggctgaaat aaaaaggaca 137160 gctgtgttaa aaggaagtag agaaatcaga accctcatac actgctggtg caattgcaaa 137220 attagggcag ccactttgga aaagagtttg gcaattcctc aacatgttaa acacggagtt 137280 accctaggaa cccagcagtt tcactcctag atatatagcc aagagaactg aatatatatg 137340 ttcacataaa atcttgcaga taaacgttct ttgcaacagt attcatgtca caacatgaat 137400 ataccttgaa aataccatag taaataaaag aacctgtaca caaaaggaca catagtgtat 137460 gattcccatt tatatgaaat gtccagaata aataaattca tagagacaaa gcagattagt 137520 tgttgccagg ggccaggaaa gggaagaatg gggaatggct gctaacaggt taggatttct 137580 tttggggatg atgaaaatgt tctaaaattc gatagtggtg atggccgcac aactgtgaat 137640 atactaaaaa ctttaaaagg gtgaatttta tagtatgtga attatctcaa taaagctatt 137700 aatagttttg aaagttagag aatatgtttg gtatgatttt tttttaaaca ccgcctcccc 137760 aaaaggaaaa aagctgtatg tatatcagta cctttacagc tatcttacat tttatatttg 137820 attggtaatt tccttccaag catttctttc cccctacatt taaacacatt taacaactgt 137880 taagttttag aactggctat gaagggaaga gaaacatttc atttcttctt atacttaaaa 137940 aaaaatagct ttttattttt cttttctata tttcctcatc ctcaaaaata gattctacac 138000 accaatattt gagggatggt ggggcaacta ccacaaaata caagaggctg tcttttggaa 138060 atgtaaaaat gttagaattc ctaggaactt gtcttgattt atgggactaa cctaatattt 138120 aaaactgagc ccatgctggt aaatctgggc tatacagtca tacatacata gaactgtggt 138180 atcacaacac atccactgtg cactggaaga gtactataat ctccttataa tgtgcacctt 138240 ggctctcccc tcccttgcgt tctttgacat tttttttttt aaataaggca tgtttatttc 138300 ttatttacct actaactaca gaaggtagac tcacgatgtg ccaatattaa aatgttattc 138360 cccattaaaa tacatttact taagtgtttt attacatgac ttaccagcaa tggaagaatc 138420 tcatctgaga gtagttctca actgtcatct atgaaaatct ttagaaatac caaatcatca 138480 gaattacttt aatttcctgg cttttaatca taaaacattc ctactggtca acaattctac 138540 aatctgaaaa gagacatctg taccatatag tcccaatgat ttattattct gaaattttcc 138600 tctgggttat ttttacacta taattagagt tcaaacttcc atagtgccta gcctaaaatt 138660 aaacctagaa ttatgccaat ttatgcctgc tatatatgca cacacaaaag acttataatg 138720 caacatactg aaagaactaa aggtaggtgg gtttttcttt gaaggaatca tagctacata 138780 atttcaagtt taatctgtta catttatctg cctgtaaaca tgcctgtagc atgtaaactc 138840 ataaaacgaa aactgattta gtaacaaaaa aaattagctt ctaatttaac ttcaaaatgc 138900 ttttcaaaaa atcgacccca tctaattcta agtgaactag accacacttg atagaaaact 138960 gttgttctaa aaaccatacg tacttaacat aaatagtaaa catacgagaa catttagtct 139020 tctattaatg tcttacaaaa tacttcaatg tggcctagcc tggttataat ttttttcttt 139080 ttttttaagg gacagggtct ctgtcaccga ggctggagtg cagtggtgtg ataatagttc 139140 actgcagcct ggaactccag ggttcaagca atcccccccc acctcaggct cccgagctgg 139200 gctaatttta tttttcatag ggataaggtc tcactttgtt gcccaggctg gtctccaatt 139260 cgcggcctca agtgattctc tcacctctgc cttacatttc cttttgagct gttattatca 139320 actggagtaa catttctagt tgggggaaaa aggaactgat ccttatcaat ctgtagatga 139380 atacttattc agcacttaca aataactgaa tgtgggcatg aaaaaaagaa tgacagatga 139440 taaacattta ctgttctcac agaactatca aatacaggaa taagtaaatt acctaatttc 139500 agttgagata aatacgactc agaattcaat aaacagtata aggtgaggat gctagaaatg 139560 cccacataat gctgacaaac tacacattgg catatccatt taagaaaaga atttaccaat 139620 atctagtaac cagcaatttc acttctacgg ttctttccaa aacacctgca catacactca 139680 cgtaaaaata aacactgcag cattgcttat aatagcaaaa agaaaacaac tcaaaatatc 139740 catcaatagt gggatacatt ttatctatgc ataaaatgaa gtgccagaca acagtgaaac 139800 tgaataaact acatctacat acatgaacat atacacctca aaaacttgat actgagttta 139860 aaaaaatcaa gctattgaaa gacagtgcta tacatatctg taaaaattta atacaaaaac 139920 caccaccaca tatcacttat agatacatgt acacatgtat agtaaaagta taaaacaagg 139980 atgtgaaata tacttaagaa tctcaagaca gttgttactt tgtgtagaga ggggtaacag 140040 gacttgaaca gttggggttg ttaaaagtca ttatgtaact ggcatccttt cccccaaggg 140100 ataaaaatgg acataattta catttatagc tggtggataa atgggcattt gctatgttgt 140160 tttctggatg tttttaaaac tttacaatta aaacatatac acttatttta aaaacaaaca 140220 aaagacacat tagcatataa tgtccaagct gatatttacc ttggaagatc atctaatata 140280 aacctcccta cttcactaaa aaaaatcaga aaagatgtca gaataaaaat atgatacagg 140340 ctggacgcag tggctcatgt ctataattcc agcactttag gaggccaagg caggaggatc 140400 ccttgagccc aggagtcaag accaggctgg gtaatatagt gaaacttcat ctctacaaac 140460 aaaacaaaac aaaacaaaac aaaacaaaac caaaccacca aactttttag taagaatgta 140520 atagggttgg tgtggtggct catgccttta atcccagtac tttcagaggt cgaggcgggc 140580 agatcacgtg aggttaggag tttgaaacca gcctggccaa catggtgaaa ccctgtaact 140640 actaaaaata caaaaattag ccgggcgtgg tggcacacgc ctgtagtccc tgctactcag 140700 gaggctgagg caggagaatc gcttgaaccc aggaggcgga ggctgcagtg agatgagatc 140760 gcaccactgc actccagcct gggtgacagc gtgagactct atctcaggaa aaaataaaat 140820 aaatacgtgt gtgtgtgtat gtgtgtatat atatatgcat tatatatata cacacatata 140880 tatatgtata tatatataca cacacacaca tataaaatac atatataata tatatactct 140940 tgtagcaggg caattttgga cagatactag gttatctgga acagcacttt ggggaattag 141000 atcctgacca tttaagagag aaatctggta ctgactagca atatggacaa tgtgtgcacc 141060 accctcactc cccctcccct cctaggaatg ccatgtcaaa tttagcacag gcataggcag 141120 taaaactgac ccctagttct gcctatcact atttaaaatt actttcagtt ctgagtgtag 141180 aggactgtcc ccacagcaga tatctaaaag caggcctgaa agaactagaa agtagttcat 141240 tcctcctaaa actgtacatg aaaaaacaaa attaaaaaat gaactgagag caaacattta 141300 tgctctctta taattttcaa tccaggattt aagaaattat ttaacatcag ctgagacgtg 141360 accaacctat tctccagttg agatccatct atttttaaat tcactccccc acctttcatt 141420 cagcctaaaa gaggaaataa gaatgggaag gtggggagga cttatcccat actgagttaa 141480 ataagaccac aagatctttt catttttaca atatttgaaa tacagtacac tgagcaataa 141540 atttaaagaa atatacacta tttgaaatgc ataaatgttg ctttatgtgt ataaaagatc 141600 aaaattagct cagttcttct aatacactac acttaagcgt tcttcgatac tatcgtcaac 141660 ttttcagaaa tattcccatt ctgtgaagca ggatgtattc ctaccttatt caccagactt 141720 tatccacgta acttcctatt ctcccactct attctttaaa catgttcaac atgttacaga 141780 gatggcaaaa tgtgttaaaa aagggaatga gaatgaagca gcttaagtaa ttaggaaaac 141840 tttataattc ttagaaactg aatttggatg atctttaaaa aaaaaaaaaa aagaaaagaa 141900 aatctgctat ttgagatgaa gtgtcgcctg cccaggctgg agtgcaatgg cacgatctcg 141960 gctcactgca acctctgcct cccaggttca agcgattctt gtgcctcagc ctcccgagta 142020 gctgggatta cagatgtgtg ccaccacgcc tagctaattt ttgtattttt aggagagaca 142080 gggtttcacc aagatggcca ggctggtctc gaactcccga cctcaggtga tcagcaggcc 142140 tcagcctccc aaagtgctga gatcacaggc gtgagccaag gtgcccagcc taaagagcat 142200 attttcaatc accaacacac aacatgactg ctgacttcag aaaactagga aagaaaaacg 142260 ttacccaatt aatcgttgtg tgaaatagga tttatccatt agtatacata tcacatacaa 142320 taggtgcaca aaagattttt tccattccca aaacaaaaac ttaaaatatt taacaaagat 142380 aatataaata tccttattta tagcacattg taaggttatc aatattggtg catataacca 142440 cagaggcaca ataaatagaa ttctgaggaa aaatgtatta agacaataaa caagctggaa 142500 ataaccccta tttcccctta tgacccatta gctttatata gaaaatactg ctgtgcactt 142560 catcctttgc tttctaaaga acagcattat ggttcacatc tgttaagaga cagaaaagta 142620 tttgttggaa gtatgcaagg aagaaattcc tgtactgtta cgtgcagtgc taaaggaatc 142680 atctgagaag aaaataaaga acatgagttt aacatgagct ttagagaggg aacaagagtg 142740 caagaaagcg acaaaatgtg acatatgtcc atagtgaata catggtattt tattttcagt 142800 atttgtatat ttaatttgga ggtggaaaga ttcagaattt attctgcatc acaaagatta 142860 taaaaatata tgagttgggg tgttggctac agtacacaaa ggcaattcta agacaaacta 142920 ttaacagaag cttgaaatgg ataagccatc ccttctgcta tgagacagaa gtcattacac 142980 gaaaagaatc tgtgtagaag cacagcaatg gtagcatctt cattcagccc acagctgtgt 143040 aatttgtgtg caagagtgct tgtcttaaac atgaaaagga acatcctgaa ttgctgaaag 143100 tatatacaac gggcacacat ccagaactag aaaagaccta ccaagcctgc atgctatgaa 143160 gagataggtc aaaaaatttt tctcatgttt ggtttttata actaaagtct gtgctagact 143220 aacctcaatt gatcctgagg ggtacagatg aacttctgga acacaatgaa ctgttaagag 143280 tcacagcttt agactctaca ctgtccagcc aacagtttca agaaaaattt tatccttctt 143340 gtatgagtgt tcagggatca tatactacct ctatgctctt acttgaagca cagatacaga 143400 ccttaataaa taaagtctta catcagactg tcttctataa tcacatgtga ttccttacac 143460 gagattcctg ttcagatttc ctgaaaatga actataggaa taatcttatc caatatgagt 143520 ctatgtcccc taaaaatctc ttttcctttc aggtcaatct tatgattcac ttgccataga 143580 tcagattaac acaacaggtc tgatacagca aattacaaaa gagatttgac ttttgattaa 143640 tacactgaat aacgtaccac aaactattaa gatctattgt ccatgtcaaa tggagttcac 143700 atattcagaa tgaattcaca cactaaaaat tttccaatac aaagtttcta aaaagttttt 143760 tctttttttg agacggagtc tcgctctgtc gccaggcagt gggtatgatc ttggctcacc 143820 gtaacctccg cctcccgggt tcaagtgttt cccctgcctc agcctccaga gtagttggga 143880 ctacaggcgt gttaattttt gtgtgtgtgt attttagtag agatgggatt tcaccatgtt 143940 ggccaggatg gtctcgatct cctgacctcg tgatccgcct gcctcggctt cccaaagtgc 144000 tgggatgaca ggcgtgagcc accgcgcttg gcctctaaaa agcctcttaa tctacatttt 144060 caagaatgat cacatttgaa aagcatactc ttttaaaaca aagcaactat caccttcatt 144120 tgacagaagg aggaacaaac gcttcaaaag ctaaataacc tgctcatgac cattaggaag 144180 ctatagttaa aacaacctca agaccaacct ccttcctcca tttcaatgac tctgacacac 144240 ttaaaatttt ataaataatt ttagggatta tcagtcataa ggcttagaat caaatagtaa 144300 cgactcatgt acaaagacca gtattttttt aaaatgctca gctgggcatg gtagctcaca 144360 cctgtaatcc tagcactctg agaggccaag gggcttgagg acaggagttt gaaaccaact 144420 tgaacatggc aagaccccat ctccacaaaa aataaaaaaa ttagccaggc atggtggcat 144480 atgctaatct cacctactca ggagggtgag atgggaggat cactcaggcc tgagactgca 144540 atgagttatg acagcaccac tgcactccaa cttgggcaac agagcgagac cctgtctcta 144600 aacaaataaa taaaattaaa caaaaagaaa tgctttggga ggccgagacg ggcggatcac 144660 gaggtcagga gatcgagact atcctggcta acacagtgaa accccgtctc tactaaaaaa 144720 atacaaaaaa actccccggg tgcggtggtg ggcgcctgta gttccagcta ctcgggaggc 144780 tgaggcagga gaatggcgta aacccaggag gtggagcttg tagtgagctg agatccggcc 144840 actgcactct agcccaggct acagagcgag actccgtctc aaaaaaaaaa aaatgctaac 144900 tttatttcac tctcagatag gcctaataat taataagctt ctttttgaat tattatccat 144960 aatggcattt acctgttaca gataactcac atcaaagcac taagcaacat ttttgagagc 145020 aaatgaaaac aaaagctgcc aaagaagctg tgtattaata agtcatttca ttaaaaaaaa 145080 aaaaacttgc caggtgttgt ggctcatgcc tgtaatccca acacactggg aagctgaggt 145140 aaaagcctag gagttcaaga ccagcctggg caacacagtg agaccctcat ctctataaaa 145200 caaaaatttt taatattatc tttttaaaaa ggacttattt atatagcatc tttaagtatt 145260 tcaaacattt catgtttgga ttatggggta tgtttctaga attaacacta tttctattta 145320 aggtaatttt acatcatttc ctttattaga aaaaataaca gatctgtgga tggcattttg 145380 tgaaggctgc cttctattaa tagtgtataa aacagtcatg tatctccaaa acggtgggtg 145440 agtaatcaca aagcaagtgt aactattcat cccaaaaggg aggacagaac atgtgccaat 145500 gtgtgcagag tcctgaacta gagacttgga ttctagttct ggtcctgaca cctgggtgtc 145560 tttcagaaaa tcattttaaa gctttgcact ccaatttcct catgtataaa atgactggag 145620 cagctgacct catagacaat cctacttagg tagcatctat caatgtattg ccagaagaca 145680 gaatcataat catgcccccc aaaattagag tatttgaaga caaccgccaa agtaaaaatt 145740 ttaaattctt ttttattttt tttaattttt attttttttg agactgagtc tcactctgtc 145800 tcccaggctg gagtgcagtg gccagatctc agctcactgc aaactccgcc tcccgggttc 145860 atgccattct cctgcctcag cctcccaagt agctgggact acaggcgccc gccaccacac 145920 ctggctaatt tttgcatttt tagtagagac ggggttcacc gtgnnnnnnn nnnnnnnnnn 145980 nnntttttag aaactttgta ttggaaaatt tttagtgtgt gaattcattc tgaatatgtg 146040 aactccattt gacatggaca atagatctta atagtttgtg gtacgttatt cagtgtatta 146100 atcaaaagtc aaatctcttt tgtaatttgc tgtatcagac ctgttgtgtt aatctgatct 146160 atggcaagtg aatcataaga ttgacctgaa aggaaaagag atttttaggg gacttagact 146220 ccttacacac acacacacac acacacacac acacacacac acacacacaa atactaatac 146280 actacatgcc agatactggg gtggtgggct gggaccaagg catgaagtaa taatgcatgt 146340 gccaaagggc tgaacttttt aaaatgagta caaaagtaaa ttttcagagt agcagctggt 146400 gggtaggagg tattgagtcc acagaactgc tcttagattg gaagggcatg ggagaatgaa 146460 gttccattat gtgatggggt tttacacaca cacacacaca cacacacaca cacacacaca 146520 cgcacacaca catgaatgtg agaaagtcac tcaattataa gcattcaaaa agacagacag 146580 ctttcttgtc tttgtggcgt cagtacctag ctcagctcat agaagccaca ggaggaacct 146640 aatcaatgtt agttgatcat ttactgattt accaataact aattcatgac tgctctagtg 146700 ctgtggtctg aatgtgtccc ccaaaattca tgttgaaagc ctaaccgcca aggtgacagt 146760 attaacagct ggggcctttg ggaggctttg ccctcattaa tggaattaat gcctctataa 146820 aagaggccct atagagcccc ctctactctt ctactacatg aagttatagt gaaaagacag 146880 ctagctgtct atgaacaagg gaagagggcc ctcactaaga tgtcaaattt gtcggtacct 146940 tgatcttggt tggacttctc agcccccaga accgtgagaa ataaaacttc cgttgtttat 147000 acgccaccct gtctgtggtg ttttgtaata gtagccagaa cagactaaga catctagtaa 147060 cgcattctct ggtaaacact aggaattcct ggccttaaag agttcatagc taatgagaaa 147120 agaaataaac aatataaagg ataacatgct gtagtccatt atatacaaag tgcttccaga 147180 ccattcagaa aaactggata ggaagatttc taaggtaata cttattgagt gcctgcgtgt 147240 taggcgtttt acatacttta agcctcacaa ctctggggaa gtttcaccaa cccattttac 147300 aggtgacaaa actgtggctt accaagatta ataaggtcag aattaaaagt agggtctaat 147360 tccaaagaca ttaccactat acataccaat ttgtcttgtt actacatttt atccttacat 147420 ttggcagtga ggggaaaact caaaaccagt caaaaaaact tttgtcctga accagcataa 147480 aaagagcacc taagacttca tccagtattt tactgaaaga tcacttctaa aagtttgtct 147540 tcaccccgat ctaaaaatta gaaaactaat tttctttcag cagctgcata agtacataat 147600 gtaatgtttc tacatttaga cctatacaat tataggtcta aacaaaatat gtgtaacacg 147660 attggagaac attagcagtc atttaagaaa atggacattt ggaaacatca ttttaagagc 147720 ttgggatgaa aaactttgct atgacctata catctggatc attccactga ctgacactga 147780 gagaaacagt gtattatcac agtttacaca gcaaattttt ttggagggga gaaggaggtg 147840 attgaaatag aaatgatatg aagtttaaga aatacaactg attagatgtc acatgtcaaa 147900 gacactgtag gtacccaata aatactgtta aatggactgg acaagtggga tgagaacact 147960 ttttccccac acctctgact agtacgtgcc tttcttagga agttattttt tcagccatga 148020 aaaaaaaagg gcagaattta ggacagataa aacacaagta gcttataaat cctctgaaag 148080 gaaatcaaaa cacagtattt tgtatctctg tataaagtta agctcctcag ggacaggggc 148140 aatgtccaga ggatggtgag catactactt agcaaactaa tgcaggttaa taaatattga 148200 cacagtaaga cttgcatagt ttacattcta attttgtaaa gattatgagt tacctcttca 148260 tattctgttc ttgtatttct cctgtgtata ttataaatac acaaacattg caaattattt 148320 tttgaagcta tttcattttt ggtcaagact attagcgttt cttaaaaggg tttctggtca 148380 tccttagggt ttatcagtca catcattaat attgtattca tttcactaaa aatgtggtaa 148440 gtagcttaga tttaaaaaca ggatctaatt tcaaagctat ttccactata cataccaaga 148500 taaaactttc ttctctctcc taaattctaa atttcacatg atttaccaaa tcacctctta 148560 agagtactta ttggtcagca gtgtgagaca aacacttacc ccacttgtcc aatgtattcc 148620 acaagattga ctgggtacct ttgtgtctct gacaggtaac ttccgacagt tgtatttctt 148680 aaactttaag tcgtctccca aaaaactctg taatttgctg cttctctcaa tattgcaggc 148740 agtgaaatga tccaaaatta cgcgtcatat ccatattcct tcatgattga ggttaactat 148800 gcactgcaaa ccccatatgc tattacttta tattttcagc agcaccctag cctcttaata 148860 atctcaaaca gattttgtac tgttactaat ttagcacatc cataaaaagt cattaaaaaa 148920 atttagacgc taaattctct ttcaaggttg ccaagcttca ccactgtatt aaaattattt 148980 ttaaaatttc aaggactaag gcatttggta cattcaattc cacctttacc aacaaaagcc 149040 tttatcacta agatgaggaa agcatccttt tcattttctc cagtgaaaag ggggaaaaaa 149100 aaaaaggcca actgcttgca tgcaggtctg catataacac agcagtctct ggcaaagcca 149160 gtaactcacg ttcaacttca gaaatcctgg tggacggcaa cacatgagta atctgtgcgc 149220 acaacccttg ggcttgacat accacttcct ccgccctccc ttcccatcaa tccaccccca 149280 aaaccccaac ccaccaagca cacggctaaa tatgtcttcc ccaagagagc cagaaacctc 149340 gaaaacgccg agaaagagct ccccttggaa ggaaagggcc tgcccttccc agtccggggc 149400 cccggctggc tcgacaagcc tctctccgag gaggcccaaa tctcgacgcc tcgcacgtcc 149460 agccccgccc cgggcccgct cgcgtcccct cgggcgacaa aaccctcccg ccggcgctca 149520 gccaggactg acagttaaga ctgcagcagc cgcggccacc aggggcctac ttctggcacc 149580 agcccctccg gaccacgcgc ccccaaacac tcgcctcggc ggcggggggc ggggaagcgg 149640 ggcgccgacc tcgccaccgc gggccccgaa ggccggccga gtgacggagg ggagccagcg 149700 ccgcctggcg caggccgcgg caacactgac ctgtcgtcgc ccccgcgcct gggctgcggc 149760 ggccgcctca ctggtcgtcg tcgccctcgc ccgccgcctc cgcccgccac cgcctcgttc 149820 cctttcgctg ccgccaccgc cggggctcat gcgggacccg cgcttcctta tccggaaaac 149880 gaggccggga aagggggcgc cggagccgcc gaaattccgg cgttcgtcgc cagccgccgc 149940 tgcctgtcca caccgggggc tgcggggccc tcctgccagg ggctacaggc cgcgagctat 150000 tccgaggagg agccgaagga ggcgccgccg cccgcagcag agcgcgccgg gtcggcagag 150060 gtgaagcgta agtaggcggc ggatggcggg cgcccgggct ggtggatggc tacgcggcgg 150120 aggggtgcgc gagcgagcga agcctggtgt gtcgggtcct ggcgaaggga aaaggccctg 150180 tcgtctcctg tagtcacccc gagcccagcg ccaccatctt gggagaaaca cggatct 150237 <210> 3 <211> 113476 <212> DNA <213> Mus musculus <400> 3 atccagggca acagggttac aagacgtccg ttgactcctt ggggggctct tgggtgactt 60 ccctgaggtc ctcagatgcc cttgccctgt ttcccataag aggaaatgtg gacatctagg 120 atgcacattg gttggcaaac attccattcc aacaagcacc tagttctaca ttctactctt 180 gggaatttct gcaaggcctg cccattgctc atgactgtct tttctggtct tttttgcagt 240 catatgacat gccaccttgg aaagcagaga accacagata tcaggtatgt ggaaagatca 300 tggctaaagc ctccccttcc atatgcccag gcccttcatg ttttggtttc aattctgagc 360 caatcggccc ttttggaatt taggaataag aaaatagtat gcaatcacca aacgaagctc 420 gatttaggct atgttctccc atgtagatcc ctagtttgca aagttttaag gaatttgttc 480 aactcctgat aatagatttc tcataatttt gacctacttc tcatggagag aagatgacat 540 ttttagtatg ttgggatctc atacttggat tcttatgtgg ccatggtgaa taggtacagg 600 atgacaacac aagcctccag ggccatttag gactcttcct ttcccatgac acagaaggcc 660 caagggacag agcctttctt agggagagag aaggattcta tgatatccaa caaggctggc 720 ctccacatga agtgttcaca aagagcaatc cctttagcaa atattccaaa gatttcaacc 780 cacagggaat tcacccatgt ggagagggtg agattttcat ttttgccttg gtttccacca 840 ccttccaaat tttcttcatg gtatcatttg gggctcttac tgaacctcac tgcagaatca 900 ctgaggaaac aatggcctat acattcggtt gatacaggga aggccaggtg taaaggaact 960 taattccact ttgattcatg acaccaaggc ccaaatttga tccagcagta gtggttacct 1020 tcatgtgtta gaggctgggc aacccattac agcttaacac aaatggatcc atggctagac 1080 atttgtcctg tgccctaggc ccaggattct cgggagattt tcagtaatca catttcacag 1140 tgagtgctgt catgcaatat agagcttaca gagttctgat gccacctttg aactttgaat 1200 aagaaaccat tggttacttt aatcacactc gaaataccta tctgtagttg tgttttattg 1260 tcctgtccat agttctttgg gagctcaact tgagtgttga tccccacaaa attgtgaggc 1320 taaggtcaca tgtgatgtgc ctattgcttc tagaggaagc agtaaagctt tgttggaatt 1380 ccaggggtcc tttgtgcttt taattaggtt tctctatggt atgcatgaaa acttgtgtgt 1440 gctgggcctg gttttagtag aagaggcagc cacaagagag tttctgcaca atggcgttct 1500 gagtgtttaa taaccatact tggaggctaa tgttcagagg cagtgaatgg gagaatattt 1560 tttcttggcc ctccaaggtc attaagtccc aaaggactgt gtgttatctc tagaaatgtt 1620 cacacactgt ataatgtcac ccgtactctt gttctaggat gctatggtga ccccactaaa 1680 tgaattctaa ccctttgcat gatacagatg ctttgcatct tttaattttg attgtggcct 1740 cttagagaga ttcttttctg ggacgtttta agcaatactc tttttacact atgcttcttc 1800 acaccttgaa gcactttaga aagatttata cccaaaaact tttaaaagca gttcaggtga 1860 cccctaaagg gaggactaaa gggccatgag ctattcatcc ctcttcttga caccctaggg 1920 tgcagaacta aagagctgga ctgaaggctt ctttgtataa tcagtaatca gaaaactttt 1980 tttaaaaaaa ttaggtcaga taacatcttt tggggccaat ttgattcttt ggctgttgta 2040 gtactccaaa actaaagatg actagatctg actactgcta aggataggat ttgtgcccta 2100 cttcagaaat tatactggtg tgagatggag acaaaaatcc aatggcatgc ttcctcctat 2160 ggatggccat ttgattcctg cctactctgg ctcctctcct ttgtcatttt tatcttaatt 2220 ttcaaccatg ccaatatttc taattacaac acaaaatatg aatcctaaaa ttttaaggat 2280 ccaagtcatt ttaagcacaa gtatctaaat atctatataa cttataataa gatactttaa 2340 atcacaaatg tatgacatca ttttgttgtt ttcaaccaca gtgaaatgtc acataatatt 2400 gtgttaatat taacccacaa taataataat ttaacaccat gcaataataa attcatatta 2460 agaaattaat ctggacagat ttcatagcat gaatttggat aaatttttaa ggaaactgct 2520 ctgacatatt ttcctaactt ttaatatgtt taataggagt ttctaaaaat gtttatttct 2580 aaatagtttg aatatataat tggtgtatga gttttcttat taattaaatt tgttctttga 2640 caatttcatg catgtataaa atacatttta ataacactta tttacctctt ccccctccta 2700 tcattgtcaa cccaccctct ttaccacaag cctctttcct gtgtttatat ctttctgttt 2760 tgtatgcaac tttgctttgc aagggtcatt tgtgtatcca tagacttcag aattatccat 2820 tgtagcctca taaactcatg gatataaaaa taatgactct ccttccaccg tatacatcat 2880 taccaatagt ttagcaaaag gtaggtcctc atgagtcctg cccccaacca tagatggtta 2940 taatagttcc agttttatac agaatgtaga tagccactgg tactatgagc taatagttgc 3000 agtagattca ttacatctag gagaaagtag ttcataggtc ttatctcaat ctcctggttc 3060 ttacattctt tttactcccc tttatttata caggatggta taattacccc tttagaattg 3120 agtacttaac tacctgtttt gttttacctg ttttgtttac ttgttttcat gaccatgcat 3180 gcttggtaac aaacaaccaa gaaagaaaaa tatgattaaa ggtcccaaat tgagatgtta 3240 tataacacag gacataaagc agtactcaac cttcctttct gatgctgtga ccttttaata 3300 cagttcttaa tgttgtggtg acacccaacc ataaaactat gtcactacta cttcatacct 3360 gtaatttttc tatcattatg aatcagcttg taaatatctg atatgcaggg tatctgatat 3420 gtgagctcca aagaggccat gacccacagg ttaaggacca ctgacataaa cggttctaat 3480 acagaatgtg tgtgccaaaa tatagaaata tgaatggtat acaacatata cttattattc 3540 tcatgtaatt gaaattttct ttgtttagta ttaataatta catctttatg gaattttctt 3600 atgagtgact gtgtgtgtgt gcacgtatgc atgcaggggc ggggcatatg tacatgacag 3660 tgacgaagaa tatcaggctc tcagtgtttc ttaggtgctg ctgaaactgt tattttctta 3720 aatctgtagt aaacacataa cttaagaaca taatattata atatttcact tatatttcat 3780 aattactctc taagtatata ttacatatgc tataaatcta aggtaatttg taggcctagt 3840 gaaacagaca tcaataagcc taatgccctt ggttaggatc aggaataggg aaaacataca 3900 tggcaagaaa tccttcaacc tttattgaaa gaacttacct attttttttt tataaaatag 3960 aaatactgga tattgtcctg agttgcctct tgtaacacag tctattgatg tgaacatggc 4020 aataatattg tattccaatg tgaaaataat tccttagttt actgagaata tatagagatg 4080 tttaccatta gaaggtttgc attaggttat tttggtgttc atgtcttttt gttccagtca 4140 tttaagtgat aaatgcagaa agtttaatct tgtagcaata tttattcctc ttacttttta 4200 taaatgtcaa attgtcccct ccaaaacttt ctttccccta ttatcatcct actacaatgg 4260 ctcagctaaa ggtcattaaa ttgacctatt cctagctttg ataaactaaa aactattttg 4320 catttttaaa tatgattttg aggctgagtg tctatttcag agtctgaaag cacacctaat 4380 cttgcgcgcg cccaactggc cagaaagaac gacgctgcaa caggatcctt ctgcacacgt 4440 ttattcagtc ctgtttcttc attctctata tctcccttgt ttatatctcc cttgtttata 4500 tcttcccctt gtttatatct cccctctcga ataataattc ttcctctaac ccgggcctct 4560 cactcttata tactctcagc cctcatccat gcacagcagg ccacgccacc tcaccaggca 4620 cgcagcttca gctaatcagg gcagcagggg catatctcca tcaaaatgga ttcaccagta 4680 tcctggtaca cctgtgcagc tctcaagatg tttgtggctt atatgaggaa gtcaggtgca 4740 agccatatga cttagctgca gtccctggag ccttcttggg attgccccca cacccgctcc 4800 tcacaaccta atatgttcca agccatatac atatacatgt acatgtacat gtacatgtac 4860 atatacatat ataataataa ctgtcttttc tttactgtca caatgaataa tggcacatga 4920 aaactatgaa acatttgttg aatcaggtaa ataaataaaa gctactaatg ttctctttct 4980 aattatactt tcacaccttt tgactcaaaa aaaaaaaaaa cccaaaacct attttgcaaa 5040 tcctggcaat ggaactgtag taaattaacc cagttataga agagctaact tgtcaggaac 5100 aggattacca agatcagtga taaacaaaat ctcctaaaga ttgagaatta tttcatgata 5160 ctaatctaca tgccctttga tagcaaaata ggatttccag aattatttaa atgtgatatc 5220 ctctttacta aaaatgttcc tacataataa tttcctacac aatagtttcc ttactaaatt 5280 tcattatcaa aatggctcca atgggcagac attagcctta aggtttcaca ttaaggagaa 5340 gtttgatatt ttaattactg tgaacagttt gatattggtt acatccaagt attgcgtgaa 5400 tacttggtta cagaaatata tagaaataaa acatgatcaa ctggtaataa agatgaacgt 5460 aactatcagt aaaattgaga aagttccatg ggaaaacaga tacaaattat acctaaatac 5520 aactgtatta gtttattata atagctattt attcttttgc aaattgattt ctttaatttt 5580 tgcttttgtt atttctgatg aataaaatat cagcattagc atcatgttta gagagagaaa 5640 tcagcatatt cctttgtcat tacaagttgt tataggctaa gatgatcata aaattagttg 5700 acacatttaa aatgagtaaa atgtgtattt atatatgatg catatatatt aaatatatgt 5760 atatatttta tacatttaaa atgagtaaaa tatatgtgtg tataacacat atatagtaat 5820 atattaccat atataaaata agtaaaatgt gtgtgtatat atatatatac atgtatatgt 5880 atatatatat ataaaatatc acataggtag atgatagatg gatagataga tagatagata 5940 gatagataga tagatagata gagaaaaagt gtgtttaagc taacacactc agaaatagat 6000 gaaaacctag aaactagggt aaagattaac ggctgaactg ccatttatac ttgctcaagg 6060 agataaaaat cagctttctc cagtgaaggg acactggata tatcaacctc tcaagggtag 6120 gcctcatgtt cagtagtagc tgaccaacat ataagagact ccacagtttt tttgtgtact 6180 tgcatttggt tacagatttt atttttcttt ttgaggtatt gtttcatttt gttttctcag 6240 tttacaatgg ttgttgtatt aatttttttt gttggtttgt ttggtctttt tttgaaggaa 6300 cttaaatttg agtgggtggg taggaaaggg gaaaggatct ggaaggatat acacaaaatt 6360 aaaaagaact aatcctttaa gaagataaat aacgctaaca aaatgaatca atgattttaa 6420 aagatacaaa tacatatatg aagaaatatg agaaaggata ctatagatta tatgtatatt 6480 aaataatagt aagagaaatt tatgaatgtg ccaatgaact cagcaattta atgaagtaaa 6540 tgaatgagtt gaaagattca aatataaaaa tttatttagt acatagataa cagaatactg 6600 ttttatcaac aaattaaatc cttattgaaa acattcctac aaagaaatat agattacaca 6660 gaattttaag attttatcct catatcacct tctagaagat ataaaaaagg aatagtgcca 6720 agctcaatat atataaaaaa gtaacacctt catcaaaaaa tgctacattt aaaatgaaga 6780 atatacagca atatttttaa tgagtataga tatatatctt tggtcaattt tttataaaat 6840 agcatctaac aatatgcaga aatatttatg attaaatcaa attaaccatt gaatgaaatt 6900 tgttttacaa tttcaaaaca aatctatatt taaaaaatca ctagacagtc aaggtaataa 6960 aaacattagg aatgtatcct tccataaaat tactatttac atgaatattc aaaataagcc 7020 aggtataggg atgtacatgc aatctcagca ctgagaaagc cataaagcag ataaatgttt 7080 atttcaagac cagcttgtac aacaagtaag accttatctc aggcagaagt caaaattaat 7140 atttggaatt ttgtaaatta accaaagact taacaaaatt acaaagaaca tttatgcaag 7200 aaaagtgtct ggctctcagt ttacaaaaag cagaatttgt gttactttta acatgtcttt 7260 atttcatact cctccctgag acactgtggt agcattgtaa atcagcaaaa tagaagccat 7320 gagagaagaa gcaaagattt gtaccccctt cccatcctaa tccccccaaa ataactattt 7380 tgacctgcta agcagttctg tagaaaaata tatcccatga tatttttagt aatttgggct 7440 gatgcagagg cttatgtgtg agtaaacccc cataccagca ttaagcataa ctaattaata 7500 taagttattg aataccatag aagataaact agttaacagt agctgagata aaaattttta 7560 aaattatgaa actgtaaaaa caatctgtct ggtaaagaga aattttgtgg tataatcagg 7620 agttctgtgg aaaatgttac cacactgctt ttggtattga gtccacatca atattcagag 7680 tgcatggtag catatgaaac atatgaagtc cctagttgct tacttcttaa ttatcactag 7740 gccctgtgta agtagtaagt tatggctaag aaacagttgt gaactacctg aataccacat 7800 gtgaaccaaa atacacatac agaacatccc ttaaaaataa tgagtgacat attgtttaaa 7860 gttatttaaa gaaatctcta tctaatcatt gcatgtgctt aaaatggaaa atacaattca 7920 gtatccacat acaacaacac acattcttta tgaacaaaaa taatgaaaaa gaacagatca 7980 accgttaaaa caaactctag gaatgataaa acatattttc atgcatatac attatatgta 8040 aaaatgtcca gtttcaaaat atatattgtc ttagttttgg ctttattccc atgtaaagat 8100 accatgacta agacaactct tataagggat atttaattgg ggttggctta caattctaga 8160 ggctcagtcc attatcatca tgccaagaag catggcagtg tcctggtgca gaagaaagag 8220 ccaagaattc tccatcttga actgaaggca cagacaggaa gaatgtctct tccacactgg 8280 gaggagcttg agcaccagca gccctcaaag cctgcctaca caatgatata cttcttccaa 8340 caaggtaaca cctattccac caatgctgca tcccctaatt ttgccacttc tatgggtcaa 8400 gcatattcaa accactatat gtgtgtatgt gtatgtgtgt gcatgtgtgt gtgtgtaagt 8460 ataaaaataa gagattaaaa cacatgtaca gaaaaagata tcaatagaaa ctggaaacaa 8520 ttcagatgcc ctcaaccaaa gaatagatac agaaaatgtg gtacatttac acaaaggaat 8580 accattcggc tattaaaaac taggacatta tgaatttcac aggcaaattg atggaaatag 8640 aaaatatcat cctgagtgag gtaacccaga cccaaaagga catccatggt atgtactcac 8700 tgataggtta atattagcca attcgttcag aatatccacg atacaactca cagatccaaa 8760 gaagttaaac aagaaagaag gcccaagtat gcttgaatcc cctaaaaagg tgaaacaatg 8820 cagtaagaga ggttagaggg aaggagaaac ctggctcaga gaggggagtg tgaggggagt 8880 gaaggggggg gcaggatcag gcaggaggac agacaggaaa gaagcccaga gggccaggag 8940 agtcagtgaa agtatgcagc tgccaggtgt tgaggttgga ggattgtcta ggaagtccca 9000 gagacctggg atgagggaac ttcctgggaa tcaatgcaga caaccttagc tgaaatgcca 9060 aaaaaagggg aataggaaag ctgatgagac aacatccagt agccaaacag gactcccagt 9120 ggacggatag ggacactaac acacccacaa aactttagat ccaaaattgg tcctatctaa 9180 aagaaacgca gggaaaaaga tggaacagag actgaagtaa tggccaacta gtgactgacc 9240 cattttgaga tgcatcccat gagcaggcac caatccctca tgctattaat gatgctatgc 9300 tgttcttgca gacagatctg agaggcttta cccatcagct gactgagaca gatgcagata 9360 cccacaaaaa cggaacagag gttggagaac cctatggatg atttagggga agaattgaag 9420 gccctcagtg aggtggtagt cccatgggaa gatcaacagt gtcaactaac ctggaccttt 9480 gggatctccc aaagacagca caaagctccc aaaggcagct ccaatcaaaa aagcacatac 9540 aggctgatct gaggcccttg gcacatatgc agcaaagggc tactatgtct ggcctcagtg 9600 ggagagaaaa tgtctaatct tgtagagact tgatgcccga gggtggggcc tgaaaaggga 9660 gggctgctct ctcagagatg tgggggaggg gaaatggagg ggaaactcta caaggggggg 9720 ggggagtcca ggagagagag cagcatttga catataaata aataaataaa taaataaata 9780 aataaataaa taaaagtatt cttaaggaaa gaaagatgtt ggacctacta gacaaaggca 9840 gtaagtcaac ttttaaaaat atattcaaag aactaaagaa aatgaggaaa tatttacata 9900 atatatgaaa atgatgcttc aagaaatata gactaaaaaa cagtaagaaa tgaccacatg 9960 aaaattactt atgttaaaaa agtaagtgtg taatgtgtat gtagtttaat gggagaaggc 10020 ttgaccagca tattcaaagc cctggcttcc atctaacact gggaaaaaac caacagaaat 10080 atacatgata taaagaactc tcaataatga atgtcagcag accagatatt ggctaacatg 10140 aatatgctct aagtaagatt atctagtcaa agtacgaaac agaaaggaaa aaaaatagct 10200 aaaatataga aaaataaact aaacaaaata gagccatagc aaactgcatt tatatcaact 10260 tatacattaa tgtgagtcca agaaggaaaa agagaaaggg gaaattttta agaatgatgg 10320 ctcaaggggc tggagagatg gctcagagat taggagcact gactgctctg gaaagaagtc 10380 ctgagttcaa ttcccaccaa ccacatggtt gctcacaacc atctgtaacg ggatctgatc 10440 ccctcttatc aaagataacg acagtatact catatagatt aaataaatct aaaaaaaaaa 10500 ggatggctca aaactttcca tatatatata aaaccaatgt accaaacaag aatataaata 10560 agcttcaaat aagataaatt caaatgcaat catataattc taaagaacaa agcatagtag 10620 tgaaactatt gaataattaa taaaaagaga atgtgaagaa tgtgtaaata tcaacaacac 10680 gctcttcatc ataaactatg cagacgagca ggcaatataa catatattat aatattacaa 10740 tataccataa tgaaacaata tttaacaatt taacatctat gaaaatacac tcatattctc 10800 atcaataggt ataatgtcca gacaaaaata acagaaaaaa ttcaggtttg aactgcatca 10860 tcagcccagg atgaaatgaa tggataagct gctgaggtct atcagataat taaagagtca 10920 ttatcgccaa tatctccaaa attattctct aaaatataaa gttcatcaac agtaacataa 10980 gttatgagta cagtattaca ttgatacaaa acttaaataa aaatacagtg aagaaaaaaa 11040 tctataatgc aattgttctg aggagtatgg atgtaaaaat tcttaataaa aatgcttaac 11100 caaatccaaa tatacatctt aaaagatcac atactaatac aaaagttgct tcattccaga 11160 gataaaagga taattcaaca tatataaggc agtaaatgta acaaacatgc acacatatga 11220 aacatagatc aaaggacaga aattgcatga tcattgtaat aaatacagaa aacagcctta 11280 gaataatgaa taactgttca tgagaaaata ctccaagtaa actatttatg gataaaaaga 11340 caataccttg atataataaa ggccataaac ataaaattat agcaaacgtc attctcaatg 11400 ggaaaagaac tgacagcatc acttacaaag ttgggaaata agtatatctc gtctctccac 11460 ttgtcaatat aatgcttaaa ttattcacct aggtaataaa gcaatggaaa tacagggtac 11520 attaagtgaa ataattcaat ccattcctat tacagacaat atggacctac actcactggg 11580 cactaaaatt ctcctcagac aggaaaacca actgatctga taaatgctcc taggaaaata 11640 gcaagatata aagtcaacac aaaaaggtat gacaacaact tttctatatt tgcataatga 11700 acattctgag cataaaactg gtcacattta caggaatgtc aaaacataac cactagaaat 11760 aaatctcacc aagaaggtaa atgatctcaa caatgaaaac cttaaaacac ttccaaaaga 11820 attcaaagac acgtggtttg taaattgtta ttttgggtat tctgagtttc tgggctaata 11880 ttcacttatc agtgagtgca tatcatggat gttcttttat gattgggcta tctcactcag 11940 aatgatatcc tccagatcca tccatttgcc taagaatttc ataaatgtat cgtttttaat 12000 agctgagtag tacattttct gtatccattc ctctgttgag ggacatttag gttctttcca 12060 gcttctggct attataaata aggctatgaa tatagtggag catgtgtcct tatgacacgt 12120 tggagcatct tctgggcgct cagtattact gggttctcag gtcctatgtc caattttctg 12180 agaaaccacc aaactaatga aactcaagaa caaagaacaa agtgtggata ctttaatcct 12240 tcttagaagg gggaacaaaa cacccatgaa gggacttaca gagacaacat gtggagcaga 12300 gactgaggga atgaccatac agagtcgcac ctgaggatcc atcccatata cagccaccaa 12360 actcagacac tattgtggat gccaacaact gcttgctgac aggagcctga tatagctgtc 12420 tcctgagagg ctctgccagt acctgacaaa tacaaaagtg gatgctcaca gccatccatg 12480 ggaccgagca cagggtaccc aatgaaggag ctagagaaag gacccaaaga gttgaggggg 12540 tttgcagccc cataggataa acaacaatat taattaacca gtactcccag agctcccaga 12600 aactaaacca ccaaccaaag agtacacatg gtgggactca tggctccagc tgcatatata 12660 gcagaggatg tcctagttgg acatcaatgg gagaagaggc ccttggtcct gtgaaggctc 12720 tatgccccag tgtaggggaa tgtcagggcc aggaagcaag agtgggtggg ttggtgtaaa 12780 gggggagcag gaaggtgagg gggagggtgt tttggagggg aaaacaggaa aggggataac 12840 acttgaaatg taaataaaga aaatatccaa taaagtcaaa gtcaaaaaaa aaaaaaagaa 12900 agaaagaaag aaaagaaaag aaacgattaa aaaaaaaaaa aaagacaccg gaagacagat 12960 tggtagagtt aataatgtaa acatagctct gcaaattaaa gtgattcaca ttttcaatat 13020 aatccctatt acaattctgg aaattgttgg aagaattatt ttaaagttta aaaacaacac 13080 tgagtacaaa aacctatgaa taaccaaagc aatcctaagc acaaacagca aagttggtat 13140 tgtcacagta tgtaacttca aacatagtat agagccattc tgataaaaca acatgatact 13200 taacacaaaa cagacacatg aacaaatata ctaaattata ctaaataaaa caaaacatat 13260 aatcccatgc tgttgtgccc aactattttt ttgttttttt tttttttaca tgagtctcaa 13320 aattatacat tcaggggaaa acatctttaa taaatggtgc taagacaact taacatatat 13380 gtacaagaat taaactaggg ctgaagaggg cttagcagtt aagaacattg agggctcttc 13440 cagaagtaat cggttcaatt cccagaaccc atgtaacaac tcacaaccat ctgtaactcc 13500 atttcccagg gttcagatac ctctgcaggc ttccttggga agccaggtag ccaagtgata 13560 cacagatata catggtcaca aaacactcat acatacaata ataaaaaaat taaaaaagga 13620 taaactaaat tcttctctct taccctgcat aaaaatccac tgaaaacaga ttaaaggctt 13680 tatttaataa aggctttatt taatgtatga cccaaagaat tgaagtggac tacatagaag 13740 cacttcaaga tatagaaagg caaggacttt ctgaaagtag gtcagaaaat gttaggagga 13800 atttacaaaa taggattaga ttacattaaa agtttctgca cagcaaaaga gacaaagctg 13860 tagagattgc tcagctgttt cagttactta ctcacataag aactaagttt ggctccacat 13920 ggtagcacag ttacctctaa ctccacttcc aggcaatctg ttgcccccag ttctctgcgc 13980 acacatggta cacatagcct cataaaggct ccagacataa aaaaaaaaac aaaaacaaaa 14040 acaaaaataa ataaataaac ttttaagagt aaagattcag actacacatg gaagaaaatc 14100 tatgctgttt tattttttta tatctgagag gggactaata ccaagaatat gcaaaatgct 14160 ataattagat tatgctacct gaacacatta agcagttagg aacattgagg gctcttccaa 14220 agttaatcgg ttcgattccc agaacaattg tggttaaaca ttgaaaccac aagtaatatg 14280 aattttccat aaagaaaaag agatctttac tgataaagct caagtgacca ataaatacat 14340 gaataatgat cagtattttt aaccattaag gaaatgcaaa tgaaaagact ggaaatttat 14400 cttatgccca tcagaaaggc tacctctaag gaaataaact agactccttg tggagatggc 14460 tcaggtagta tagtgttttt ctttcaagca tgagaacctg agtttgacca actaaactca 14520 agtacaaaga agccaggcaa ggtggcacaa gcttgtaatg ccactgtggt agaggctgag 14580 acaggtagga tctctgggac tcactgttca gatagcataa tctactattc caggtcagtg 14640 agaaactcta tcacacaata aacaaaacaa aacaaaacaa aaacaaataa gcaaacagga 14700 acaaccatca caaaacaaaa aacaagtgaa tagaaactta ggaaagactt ctagcctcca 14760 tttgcacaca catggaaagc aacaacagaa aacactgaag aggatgggag gaaagaagga 14820 ccactataca tagctagtga caatatgaat tagttcagcc atactaatca gtctgtatac 14880 aggtttctca aaaaaaaaaa acaaaaacaa aaaacaaaaa aaacaaaaac aaaaaccgaa 14940 aattacaact accatatgat ggagtgatgc cactcttggg aatgtaattc agtatagaga 15000 tatgtgaaca tccttgtcca gtaaggaaca aattaaaatg tagatggtat gaattagttt 15060 tgatgttcat gaacagatta atagacagct gggattttct tcatccataa agagtaaaat 15120 gatcacattt atgaaaaaaa ttcacaaaca caaagacaca cacagactac acatacacac 15180 acacacatga atggcatgga agtagggaaa agtattcagg aaaggcaaag agggtgagtt 15240 gtaagaaaga agatcaataa aagatcataa tgagtgggtg atgaatgtga ttaaagtaga 15300 acatatacta tcatgaaaat gcaatcgagc aactggagag atggctcagt ggtttaaagc 15360 actcactact cttccagagg tccttagttc aattcgcaac taccacatga tggctcacaa 15420 ccatctgtaa taagattcca tgccttcttc tgatttgtct gaagacaact acagcatata 15480 tatatatgta tatacatata tatatataca tatatatata cgtgtgtgtg tgtgtgtata 15540 tatatatatg tatatatata tatatatata tatatatata tatatacata cagagagaga 15600 gagagagaga gagagagaga gagagaataa aataaaagga ccaggagtca gaacagattt 15660 ggggatgtaa acaaacaaat gaataaatta aaggataaat aaaatgacat aaagcccatc 15720 actttgtact agaaatatat gctattaaaa caaaaagaaa tgatagcatc tagctgcata 15780 ttacatttct gtagtgaata actatagatg gtgtgatttc ttaaagtcag ccacacatta 15840 cacattagtt gcatccaaga tgctaaacat attagaattc gtgtaatttc aacttactga 15900 gtttaaactg gttagtataa aagtcaacca tttcaatgaa agttactata ttttatgtaa 15960 ataccttttc ataattaaaa tctattgaca caattatgga aataaaatta aagcacttag 16020 cacaagctag catatacaca cactttccac ttacatgtgt gataaggtta aacagtgaga 16080 acatcttgtc tttgatttct gtttggaatg ctactggttc ttactctaat ttattcaaca 16140 aatgtacatt tatttaaatt tccatttctt gtgtgacttt tatcagagca attgatcaag 16200 gaatgggtag gttattaagt tggacacaga aatgatcatt attattttaa taaaaaccat 16260 tgaatacatt taaagttata actacatcct tacaaaattt atggatcttt tctaagaccc 16320 aggttttatt ttacatattt ggtttcattg attactgtta ataatagttt ctttttttgt 16380 tttttattag ataatttctt tatctacatt tcaaatgtta ttccctttcc tagtttcctc 16440 tccggaaatc cctaacccac ccctcctgct ccccaaccca cccactccca ttcccagtcc 16500 tggcattccc ctatagtggg catagaacct tcacaggacc tattgcctct ccttccattg 16560 atggccaaca acccttgata ctttcctact gttgccttct actaaggttg tgattttggt 16620 ttttcattgt aatgtatggt gttgaaaaga agaaaaaaaa tgagtcttgc tcatttttat 16680 ttacatttgg tgtgactgga tgttcaaacc agtggcactg aggtgtttct ggttaaacaa 16740 tgttggctag gatcatctaa tactaattct tattgctttt gtgttgggat aagttgtggg 16800 gggtctcaat gttccctgtc acctccattg atataactat gataggaaat gaaaaaatca 16860 gttctcttct tggtaccact tgcaggtgat ggaagttcat ctggcacaag cctggcaagg 16920 aaagtgatat actattttta ccaatacatg tattttccta ttccatgctg tcctttctta 16980 taaatcataa acatggaggg gaaagtgtta ccgttgcttt gcagacacta taaatatatt 17040 taatgtcacc taaaatagaa aataacttag gacacaagta gatattatta gcagaatatg 17100 acatattgta caagtactag tcagtatagt aagtaatgaa aaaaataaca gacttgcaaa 17160 tttgaaaagg aggaaagaca tttattcata gatgacatgt ttatctataa aaaactgaaa 17220 accaaaacaa gaaccctgag attcaactag aaattggata tctaacctat aatcagagca 17280 ctgaataggc ttgtctcttg ctaattatct ttgagataca tcattctaag aagctacttg 17340 tttaactagg ttacctgcta aagttttatt taaacaccat caatgaacaa agactcttta 17400 ttctttttat cagtgacatc acttaagtac agacaatata atacttaata aagtaccaaa 17460 tgcagagctc aattttggcc tgttaggtta agtttataga taaacatata atactagtag 17520 aatgattata tatgtcttct aggaaatcct tacctactgt ttcccaaaat taagaaaatc 17580 ataccatatc acaagattag acagttgaca agaaaaacat attcttatca agaatattgt 17640 ttatgagtgc ttatttactt ggacaaaagg tatagtaaat ggcttctcat atgaaaattg 17700 aattggctat acaatacaaa cataaaaatg gtacttttct ttttgaataa gttagactga 17760 ttttcactca acctgtctaa cttgagaaca tttgacttac tggcaagggg ttccaaacgt 17820 tagacaagat ggcacaactt tgttatctac aacattctca gttaagaact gtaacagaga 17880 gagagaggag agagagagag agagagagag agagagagag agagagagag agagagagag 17940 agagagagag agagggagag agagggaggg agggagggag ggagggagag agagagaggg 18000 agagagagag ggagggaggg agggagggag ggagggaggg agggagggag ggagggaggg 18060 agggagggag ggagggagaa acacatccta aaatctcatc atttaagtaa atttacaatt 18120 ttgtgttatg ttgtatttat agcttttctt gcttcatgaa gtcttcttaa gcctacaagc 18180 cacagtttga ctatacctga atagtttaaa cctagtgttg ccttgatggc tttctatcct 18240 gataacctgt gcactctaaa gtagtgtata aagatctaag gctttactga accttagata 18300 tctcacttct catcgtttaa taattgcttt ctacatttac acacaccaat attgggtgga 18360 tatatttata attgttataa ggtaacttct gtaatccatt ttaaacttcc actattgtct 18420 ccttgcctcc cctttgaatt tacagttcac attttaaaga atttcaaaac accccttatt 18480 tttcattgta tttattagga tagctttggc caggtcaggg acatacatct ttatttatag 18540 cacttgggat ttaaaagaag aagttcagat aaaccatgaa tacataatga aaccatgtca 18600 caaaaaaagg aaaacatttt ccttgatgat attcacacta aagattgtca ctaagcctct 18660 tactttatta tttaaatttg ggggtgttga gaatgaaata caaagcctta catattctac 18720 acaagcagcc tacctctgaa ctttgcattt ggttctgttt ccactgtaat taacaatttt 18780 ttgtaggact ggagagcaaa cctaggattt aatgcatcca aggtaagcac tctactgctg 18840 tgccaaagac cctaccaatt taacatttta cataaggcag gccactttta tcacattaac 18900 ttttagggga agagggagtg gtctgttaag tctcatgttt ctgaaggata gctctgttaa 18960 gcatagtaat tcttggttgg cagcactaca accatgtaat aacataaata ttaattcatt 19020 tatggatgac tgggacatag aagctctgac atattagtca attaagccta attgttggat 19080 taatctgaag gcattattga aaaatggtag acagaacaat aggtcaccag gttgttgtct 19140 gtagccatgt cttagacttt tcatgtctct tcctggttct tgaccactat gaggtgaaca 19200 gtcttgcttc atttatcata tcttctgcca tgatgtcctg cacttgtaat caacaaaagc 19260 aatggaagca gtagatcatg gactaaaacc accaatacca tgagtcataa caactgtttc 19320 ctctttttaa attgttcaag tattcatcaa agtagacagc agatgcaatt tttttctttc 19380 atttctaaag ttttcttttt ttttattaga tattttacat ttcaaatgct atcccgaaag 19440 ttccctatac cctcctccca acctgctccc cgatccaccc actcccactt cttggccctg 19500 gcattcccct gtactggggc atataaagtt tgcaatacca aggggcctct cttcccagtg 19560 atggtcaact aggccatctt ctgatacata tgcagctaga gacacgagct ctggttagtt 19620 catattgttg ttccacctat agggttgcag agcccttcag ctccttgggt gctgtctcta 19680 aaaattcagg tgacaacaga tgctggtgaa gatgtggaga aagaagaaca ctcctccatt 19740 actgggggga ttgcaagctt gtacaaccac tctggaagta agtctggcga ttcctcagaa 19800 aattggacat agtactacca gaagatccag caatacctct cctgggcata catatatcca 19860 gatgcaattc tttagccctt taaaaacttc tctacttcaa agcatgatgt ttctattgag 19920 gtgtatgcta catatacgag agggctctta tatatggttt cttttgtttt caacattttt 19980 ctggtgtgtg tgtgtgtgtg tgtgtgtgtg tgtgtgtgtg tatgtgtgtg cgcgtgcatg 20040 cgcagaggcg cacatgtata cctatgtgtg tggcacaagg caatgactat gttctggggc 20100 aaatacatag accaaacctg gaatcccgtg aactacctgt acctgggtaa ctttcaccta 20160 gtataggatg tttaatgcca ttaattcttc agcctcttaa acctttctct ttgttttatc 20220 ttgaacacaa actatttgaa cctttgtcct attgtaacat tttgtgctat tgattcaagc 20280 cagggaattg ggtaagcaaa gcaaatgagc caacaccaag ttaaaaaaaa aattcctttt 20340 taatcgtgct ccaccaatgc cacaaacttc cttcattcat tctttatttt tctcttcttt 20400 ctatatattt tcagataact aataatctag gtaagagttt ttatttttga ccaatgtgtt 20460 atttaattga tgttttcagg tctaatattt gttgctattg ttccaatctt ttaaccttcc 20520 agtcatgtgt tatttgtttt gaatcctcaa tcattatgtt tgaatatcag ttaaatttgc 20580 agtttggtaa tctgatacat atttttatta cattcgccta attgctcaga tacttcacac 20640 atttccagtt tttccttatt aactatttgt tctttccccc tatattataa tgattttgag 20700 cactcttttg acccttgtaa taatgactta gtgtgtacta aagtagatac tcattccaag 20760 ttttttcagt cttcctttgg aaaatgcctg ttcaaagacc ctggacagag tgccacaacc 20820 tttgagccca tgaccaacac agcctttgaa acactaggga attctctcac tccaactcta 20880 cactggctag cacaatgctg gactagaatc ctgtggctat tgatacaggc agagatttga 20940 gaagcactca aaacctagag gtactgatgc taaaacagca ctaaaatatg cccaagttcc 21000 attgccacca agccccttgt agtcatccag tagtgtgtaa gagaacacag accaattcca 21060 tctggcagtt gctacatatt cttatgtgat atgagtaaac tgttgcagct caaatcacag 21120 gagggtcttg cttcagaggt catactattc tgatcaataa aggtttttat gtcatgccta 21180 gttggtattg gggtccatag taaaacttac atgcttattt atccaattca ttcactagct 21240 atcaaactgc atacatatac agttttgctt ataaattagt tggtggatat tttgtatgtc 21300 tttacatggt gactattttc aagagtgtgg cttttaaaag ttggtagaaa gactgctgga 21360 gaaatggctc agtggttaag agtgccaacc gttctgcgct ggagagatgg atcagtggtt 21420 aagagcactg actgcccttc cagaggttct gagttcaatt ctcagcaacc acatggtggc 21480 tcataaccat ctgtaatagg atccagtgcc ctcttctggt atgtctggag acaactacaa 21540 taaatacacc ttttttaaaa agcacaaaaa gaatttttaa aaaaatgtgg aaagcttttg 21600 tttgaatact tcagttcatt tggtgatata cttgctaggc aaataatcaa gtcataccga 21660 ttctctttag tttactgagg aaccaccaac ttcttctttc catatcagca tgattttaca 21720 ctcatattag tcataaacat tctatatttt tccatactta ccaatatatt tcatctttga 21780 agagaaaggc catttagtgg gcataataaa gcatctgatt ttggatgtaa tttgcactca 21840 actaaggaat agtaaaggag agcatccttt caagttcatg ccactaagta tatgtatgct 21900 ttagcatcta accgtttaga agtttttgct tggttcattg ttggactcga ctgtttttgc 21960 tgcagaatta ccatgtgaca cagctattcc atacactgga tctttatcag atgcctatga 22020 tttggttgaa ccaaaaacct acttgctctt ttagtcttta tcttatacct gaaagttaat 22080 tttaaaattg aagattacaa acattttgtg aagattgagg atattcataa tacttaaacc 22140 ttttgttcat ttttagaaaa aatggtgatc tatacttact cttttttaag tgaaaataca 22200 attttatata aatacttttg tttatttact gtttggcata caataaaaac attaaaatca 22260 tcgagcctgg agatcagttt aattttaata ttatatacaa caattctagc tctgatccca 22320 cataccaata cataattata ctcatatatt atgcacacaa cttatctata attgctacaa 22380 gttttcttga atcaatgaaa aacggtgaaa ccccacgtac aggcagatta ttacctaatg 22440 acctttcctg ttatttctat ttattcgaac tattgtctac tgacttttgt ttcagcttga 22500 catactctac ctgttataat tacagaaaac gttttaagtg gaaacagtag attctcaaac 22560 tcatatcaaa atagtgggct tggttatcag taatttgaca caaagtgaat gtttccttct 22620 tggagttatt taagctcttt gttgaggtag ggttttcatg tagccttggc tggccataaa 22680 catatgtatt caaaaaagtc cttgaacttc aatttttttc tttcagtttt gttaatggtt 22740 acattatatt cttttggagc tttgatattt acagctttgt aaatactgtt atgttgcctt 22800 agtcagttga ctaatcccca cataatattc cttgtttcct ctaagtacta atttttaaag 22860 tctctacccc tttcccaaac ctgatatata tcttgctctc tgccctaatt cactttgtgt 22920 tacatttgca tggaagggcc ctttttctca atcttttact gccaacctgt ttttttgttt 22980 ttgttttcct ggttacttct gctcttttaa tttattgctc gtatatgtaa atgatcactg 23040 acaaatgttt gctttatata gtttggtcct tgtgtgtctc ttttttttct tttttttctt 23100 tttttaatct tttactgttt ggcttgcgat ttcctccaat acagccatta atactcatct 23160 cttttttggg ggacggaggg taatgtcaca ttttggctcg ttgtttgctt ttgtgtgtgt 23220 tcttcagtat tctttgtaga aaccataggg cattatatac attcttccta atataaaaac 23280 aattttcatt gaagtactgc ataagggaca aatctaaaca ttgtataatt taaatttaag 23340 catttaggaa atagtaattc aagttccaac acttgttttc taataccttt tctttgcttt 23400 gacattctaa gagtgacaaa aaaagtatac cttgtaacta ttcaaaatga tcaatgaaag 23460 gaagaaaaca gttaagttgt aggcctagga acatacagta attaaccata atgaacaaag 23520 tacagatgaa atagatgaat aagctaagta cagtagattc agtacttagg atcactgatg 23580 ttttatatcc agagaaccct acagtaatca tatccttcta aataattttt cacatggctt 23640 ctatatgata cgatgatgca aaaacatttg agctataaag gacttggaat cctttcagtt 23700 ttaattattg attctcacat ctaaacttaa atttgaactg acagattaat tgcaagaggc 23760 ttcatagtgg actactttat ttcaaagtac cacaaattac acctttataa aatgtacata 23820 taacatgact tttgttaatt tctaaaattc ttcagaaata ctgggtttac caaccaaact 23880 gaatactgag gttgtttaat cttaaaccat aacctgagtc gaaattgttc cttccacatt 23940 aatcttattc taattattta tttaaagcag gatcttacta agtagccctg gccggcctta 24000 aacacaagag atcctcctgt ttctgcttcc cagtgctgag actaaagtca tgaactaacg 24060 ctatctgtat tctcttaaaa aaaaaaaaaa aagacctagt agtagtgatt tctcaaaact 24120 tttacttaag aattcctctt aatattgctc tcattctttt tagaaacttc cctggatata 24180 aaacctcagt gttagtgttc tcatcctata cctccaccct tcactctttc tgcttctgta 24240 ccctcctttc agttcctcct cttaactttg gacatcgaaa aaacaagcta tccaatcatt 24300 taattggaga cacatggata ttagttgctt ctttttgttg ctttcaagat tctgtctctg 24360 gattttggta agtctgatta gaatggatca tgataattac cttttatggt ttactctaga 24420 ctatactgga tatcatatgc atgtacattt gtgcctcaaa aaaaaattgc actttttcca 24480 gctattactc cttgaacgtt cactcttagg gaaaatttgg tgcaaataca attagaataa 24540 taaaatcatt taaaatggga attttgcttt ctacagctct gtaaaggtta tttttctgat 24600 agctccatag catacaattg tctcaaaact attgttctaa gggtcttgta catcctaacg 24660 aagtgcttta tcaatgaact ataccaatga attaaatcaa ttataccaat gaattaaatc 24720 aacaacccgg ataaccctac aatgacttgt tttagggttc agattgtggt atgttatgac 24780 aaatgcttaa aacacatttt tttttttaaa ttgtcatttc actgttgtgt gagatgctcc 24840 atgtcactta cagtagttat ccatggtgtc caagtaatta tgggtttatt gttgtcctac 24900 taatgactca aagaggttat tttaagattt gcaacttatg caatgtagat atgtcgtttt 24960 tcttgtagtc ctgttatgaa aggttctaga ttcttccagt aatctaggac tgctcttaag 25020 tatatagaga ggtctgtcac ctgttttcct aattttttag ttagctgcat gtttgtctca 25080 aagcgtattt gctattaaca tgctcaactt ttttgagaaa acactaagat ttgtttccat 25140 cctttaaaaa atcatttttg atatgcattt aatatgtatt taatatgtct tatacattga 25200 atagttaggc ctttatacaa atccaactaa aattttcttt gcaatgtaga gtttatatta 25260 taaagtttta tcactttgtt attctgttca ttagcaccac tatatatttt cccgttgttt 25320 ctgcttttat ttaaattgag cattgtatta gttccctaag gttgctgtat tactgcaaac 25380 taagtgacta aatgacatag tgcaaaacaa ttcattgtgt taattctgga gattaggcat 25440 ggtaacattc aaacaaacaa acaaaagtat tatcagggct ttacctaaaa cctgtatgag 25500 aatcactgtc tcttccaggt tctgattttt ttcacttttt aaaagtaatc tttggtattc 25560 ttcatcttgt agaaacaatg cccaatctct tgctccatat tactcatttt cttcctattt 25620 gtgtttgctc tccttatata gtaaggacat caggcaatac taaattacag cttattctaa 25680 agccacaagt ctcaattaaa tacaactgga tagatacttc caattaagta cctcttcaca 25740 actgtcagat atggcaatct aaaatctata tgtatagttt accaaactta aaacttctgg 25800 taatcttcaa aattatttgt ctctgacttt cttcctgtta aggagctttg atttacacat 25860 gctacagaag aaagggccaa gttgttgctt cgcttgttac cattatggta gctagaagtt 25920 agcctttgcc aacattccct gtaaaatagg aacctgaggt taattgtcat aagtacctaa 25980 gagaaatacc tgatcaacgt ccaaattata tcttcatact ctgacagctg agctgagttt 26040 aaaaaattat agtaccagtg tcttaccggg ttgacaaaat gtttttaggc atttgttgag 26100 ttttagatat gagactctca aatttgagtg gttatatatt ttcataagtt ctatcaaagc 26160 taattataac acaatttcaa agagttacaa gaagctattg actcactaga aatcctgcca 26220 gcattctgct caccttcgtt aggtatccct ttccaggctc acctccattc ctctctatac 26280 cataaaacac agaaaggaca aagctcagat tgcaataaga caaatgaatt gccttctcca 26340 ttggcttttt catttcccct tctgattttc taggacaata catttattaa tagttaaaag 26400 acaaggccag tgacatggtt tagcatggaa gtggacttgc tgctatacct cacaatgtgt 26460 atttaacccc attagtcaca caatagagaa ccaactcttg caaaatagtc tacatatgaa 26520 attccattaa gaatgatatt tgatatacta caagtggcag aaattttcgg ggatacacta 26580 ataaaaagtg acaggagcac actgctagtt ttgtagagag cttgggacag tctgagatac 26640 agaagaggaa tgggggaaag agtagggttc tgggtaaatt acacatggcg actatcagtg 26700 gatcccacaa atgcgcactc gcacgtgcgt gcacacacat agtaacaatt ttaatgaaca 26760 aagtataaaa tgctagtcct ccactagaaa tgactagtat tgtatacaag gatatcttcc 26820 caattttttt tttttttttg ccataacaga catgtaactg aaatattacc ttttatgaca 26880 gaaagaaaaa aaaagaggga aaggaaaggg gaaaggaaag gggaaagggg aaagaggaaa 26940 ggggaaagag gaaaagggaa aggggaaagg ggaaagaggg aaggggaaag aggaaaggaa 27000 aaagcaaagg aaaagcaaag gaaaagcaaa ggaaaagcaa aggaaaaagg aaaggaaagg 27060 aaaggaaagg aaaggaaagg aaaggaaagg aaaggaaagg aaaggaaaaa ggaaaggaaa 27120 ggaaaaagga aaaaggaaaa aggaaaggaa aggaaaaaga aaaggagagg aaaggagagg 27180 aaaaaggaaa ggaaaggaaa aaggaaagga gaggaaaaga gaggaaagga gaggaaagga 27240 aaaaggaaag gagaggaaag gagaggaaag taaaaaggaa aggagaggaa aggaaaaagg 27300 aaaggagagg aaaggaaaaa ggaaaggaga ggaaaggaaa aaggaaagta aaaaggaaag 27360 gagaggaaag gagaggaaag gagaggaaag gagaggaaag agggaagagg gaagagggaa 27420 gaggaaagag gaaagaggaa agaggaaaga ggaaagaaag aggaaaggaa aggaaaggaa 27480 aggaaaggaa aggaaaggaa aggaaaggaa aggaaaggaa aagaaaactg agttcatacc 27540 actaagctca tcactaaaga actggaagtt taaagtgtta ctagataact aaagagtcag 27600 caaactacag gtttatgtcc cctacaagtg ctgttatatg tgacatacat gacaatttca 27660 gattgttccc attttattat ttcctcttat gagttggtta tgtagaaaca gaaaaagcaa 27720 aaatggtaga gatgaaaagc aaaaaacaaa caaacaaaca aacaaaaacc ctaaaacctt 27780 acataaataa tggtttacac atgcaaacta aagaacttgg aagaataagt taaaagttgc 27840 atagtactga acagatggtt taaagttaca tataaaaaca tgatggattt acccactatc 27900 atctaaggaa tgagaaacaa gctggttttc cttctgttgc tttcccatac aggtgtgccc 27960 ctaaaaccag tagaggattt cgttttccct ccacagtagg aaagtgtaag gagtatctga 28020 atcggtagta aagctgcatc caggatgagt cttcatacac acgaacaatc tttgtaatga 28080 ttttttttct tagcttttta ttgggtactt ttgtagaaat ttgcatgtat ggtctggttg 28140 gctacccagg atctttatct ttgcaatcat ttcatctata cattctttcg acagatgtat 28200 tacagcctgg gaattgagga ttaaaaagaa aaaagtgaaa gaaaagttga aaccactcct 28260 actctaggac attatcaatg agaaattgag gcaataacta aagcacatac acaaatatat 28320 atataaatac agatgaccta tatgaactat atctattcag agaaacacag cataaagata 28380 tattggtccc aaacactgta tttggtgttc ttggtgggag taggtaaaag atgcaagagt 28440 tttggaaaca tcttctaaaa tacagttgca taataggcta acttctacta ctcaaaatgt 28500 acatcatcta gttagaaact agaaccctct gcacaatttt atcttgatct acttccatcc 28560 atagctagct atgtctgtgt caagaaacct ttttcatttg aatcaacaaa taaattggag 28620 gggataggga tgtagctcaa aaaagcactt gtctagttta tatgaggacc tgtgctcttc 28680 tctcacaagt ctcctaccca aaataaacca acttactact aagctctttc agatccactg 28740 agaaggatca aacaactcta ttgaggcaga gtaatggtaa attattttaa gagttaatat 28800 ttcaattatt tgaaatattt tgatttggct aactagattt cataaggtac atgtatatct 28860 ggttatttaa aagctatgat aattgatgat aattgagact ggaatggaag gcatttagct 28920 agtcatatgg gagattgtaa ggagaagaat ggaaatgaga ctctaagaca gtctgctcat 28980 tgtatggttc caaaaagtat cttcatattt tgatgtggat ccgtaagtca cagttacaaa 29040 ttccctaacc ttgcaaagct tggtatactg agtagaacac agggtcaaac aaaccaattc 29100 ctttttgtca tttctcttta acatgaattc tttgtatacc tctcaaagga tagtaattcc 29160 atagattctg tcctttgtcg tctcttttca tttcatcaca gttccctgaa agtattctag 29220 gaaaatacta acgatgactg tcatgctaga gccactcatt ttcatcttgg tgaagatcct 29280 ctctagactt acccttgaat aatctcacta cacaaagaat gtgacttagt acactgcaac 29340 tcccctgcct catctgtccc agggaaaacc caatggcatc attatccctc catcatccat 29400 atcaaatatg tgaaatcgtt cacttgactc tcctctatcc catacactat cccttctctt 29460 ttatcatgct gaatctttct gcaactatag caacaatctc attaatgcaa agaatagaga 29520 cacttaggct ttcccagttc atatggtaat aaatgtataa atttatgtct ttgcctctta 29580 agatatgcaa agtaaaatct gaagtctaca agacccatca tgatctgtct ggctgcccaa 29640 tcacatccag ctacttatct caacccaata cggcccctgt taaaataaaa tgctcttctt 29700 ttctgcctgg taaccatcta atcctttacc acgtgtcata gtttttggat ctgaattctc 29760 agtctgcttt gttgcatgat gcagatttta tgcatgtgta gtacaggtgg ggtgtagaac 29820 aagtcgttca ttttaaacac gatctctgga tttttctagc agtgagacct caagctttga 29880 gatttttctg ttcataaact tttttttaat tttacaaata ctaaacagca tagagctgac 29940 agcagtgaaa cattaaaatg accaactctt aattgaagac gaaagtcttc ctcctgctca 30000 ggtcctccta ccgcaactca aaagaccctc cctactcatt ttaacaggta ctgagggaac 30060 ttctgcacta taggaactta ttacaaagat attgtcttac ttatcaagtt cttaggatta 30120 atgcaagtgg tagtgaggat tggtgtatta ataactttat ttcagaattt accttcttgg 30180 caatcccaac ttgcttggct gttagtttcc aatgcctcct acgctgtaag cgtctttatt 30240 ggatgacact cagcttccaa ttgtatggct tactaaggaa ggaaacttct atagggcaat 30300 tttcaaaaca gctgatggct aatactttat aataatgata tatgtatggc tcatgagaag 30360 cacctacctg aactcaagac tggtgttaac tgcattttat tctactgtca aatggcactt 30420 tagacatgtc ttaccttgga atcctttcaa gagtcaatta cctctcccat gtcatccaga 30480 atctaaagac cacagaataa ctttcaaagt atattatttc aaacacacct cactggattt 30540 aagaacagtt ggaaagctcc aggcatattt ggagaccagt atcagtaata ccctgataac 30600 aaccagacaa agataacaag aaaactacag gccagtatct tttatgaata caggtgcaaa 30660 tatgctaaac aaaatactag caaaccaaat ccagcagcat agaaaatggt ttatgtagca 30720 tagacaagtg gggtaattcc aggaatgcaa ggttctttca atacaaaatt ccatcaatgt 30780 aatacaacat atcaatagaa taaaggacaa aactacatga caaccttatt agatacagaa 30840 gaagcatttg acaaaattca aaaccctttt cttgatttaa aaaaagactc agtaaggtag 30900 gaatagatgg aatatttctc aacttgcaac atctatgaaa atcccacagc taacatcata 30960 tttaatggtg aaagacctaa tgcttttcca ctacaatcag aaacaagaaa aagatgtaca 31020 ctcttgccac ttcaatttaa tatcatattg gacgtgctag ccagggcact taggcaggga 31080 aatcaaataa aaagaatcca gattggagag gaaacaaaag tatttatatt cagagatgca 31140 caatcttgta taaaaaatta aaaacagaat cagctcagaa tagctacagt atataaggtt 31200 aatacataaa aatgaattct ttctagatgt agcaatgagt aatccaaaca aatattaaaa 31260 aaaaagttgt ttgtaaaagg atcaagtgaa aaacatttaa ctcaaaaaag ccaagatgta 31320 tacactgaaa tctataaaat agcattgaaa gaaattacac acctaaataa atggaaagac 31380 actccatatt tatggattat aaaatttaat actgttaaaa taccaacata cgtcaatctg 31440 atgtatcgat tcaacacaag aacaatcaaa atcacaggtg ctttttatgt agaaattaac 31500 aaatagattc taaaatccat gtggaatgca agggacccag aacaggtaaa attatcttga 31560 tgtagaacaa agctagagaa ctaacacatc ctaaattcaa aacttactct agggctacag 31620 taattaagac agtatggtac tggcatagga agagacacac ataggacaat gggacaaagt 31680 tcaagaatcc aaaattagcc atatttatgg tcatttgtac gtgtttttga caaagatagc 31740 aagcctactc ataaggaaat tactaatagt ctttgtaaca attaggtatt gttctactag 31800 atatccacat attagagaat gaaactggat ccctaaaatg taccacatgc aaaaatgaat 31860 caaagaccta aatttaagaa ccaaaaccat aagatactta aaagacagta ggagaaatga 31920 aaacatgtac acaaagtgtt catagttgta ttcataatat gcaaaaagca gaaagaacac 31980 atgtatgcac aaccaagtgg acaagcaaaa aaatacagca tatcaataca atgacaatat 32040 tcagccacaa aagaaacagt accagtacat gctacaacat tgatgcagtt tgaactcatt 32100 gctttgtgga aggtggcgaa acagacaaaa aggccacata attgtatgac tccattaaca 32160 tgaaatgacc aaaataggca aattcatagg catacgaaga cgagtagttg ccaggggttg 32220 gagttaagaa caggcagtca ctcttaatgg gtacagaaaa ctttttacag cgatgaaatg 32280 ctctggaatt ttataaagac aatttcacaa ctctgtgaat atactataac cacaaatttt 32340 acacttttta aaatggcgaa tttttatact atgtgaatta tatctaaaag atgtgagaaa 32400 acacatctct tccatttaaa ggtggacgat ataaggtcag gttttagaaa ataagtcttc 32460 attacagaca tttctaatct ctctctctct ttttttaagt taacaagcaa cgttgggaga 32520 actgttctca ggatgtcttc caagatgtta tctaccagct gcatggtaat ttcactgaaa 32580 ccacacaacc agagataagg taggagtggg tataatccaa gtcaagggaa tggcagtgcc 32640 aaactaaaat tcagagtcat ttgactgaag gctacaaccc caaccagtgt gtactatatt 32700 ccagatacat tccttatcat tttctatgtg tttctgggta atgaaaaatc ataataatga 32760 tccaaggttc catgcatgtc agcataataa tcttaatttg ttgtttaatt tagtcatgtt 32820 tgtttttgca aaaaggaaga tgacaaattt taggtggtca tgtggacgca accttaccat 32880 ttgtcatccc ttttcctgcc tgtatgactt ttagtaaggt gtataacctc tcaagttaca 32940 gatatttatt ggctttgtga aaatgaagga ccatgtgcac agatctttag cagtcattga 33000 aaattcttgt cagaatttac aggaatttga gcagcaaagt ataagaaaat gttaaatatg 33060 actcacatat atttacagag aacagcatct ggaggattcc tctatgaaaa tttgagagac 33120 tagtcagtaa taacagaacg aattaaggta tcagttgcca tgactgctgg aagagtatga 33180 gtggcataaa gacggtggtc aagagtacac cagaagacag gatgtagagt tacaaaactg 33240 tcttgctttc aaccatctag tcttttccaa cttactgtct tttttaccct ggggcagata 33300 taatacagtg attccagaaa ctctattcaa taaatgtatg tgtatatttc ttgattaatg 33360 cttatctgcc tactgcctaa gagacagaaa gatcagtaca aggtagtttc cactgtgaat 33420 ttactcagat tccatacaaa agagaagatg ctttaaaaaa aataataata atagtgggac 33480 aatatcaaag ctaaaacaca ggaaagaagg aagggaacgc acttctgaag gcctcctcaa 33540 ctgttcaaat aaatatgatc caccaggctg tgaccaggga tatgtaggct gctattacac 33600 tatgaaggca cactgtaact aatagaagtc tttatgagta tgatactttc aaaattccaa 33660 ctgaaagaat atgtgagttg tataaagtta atctaaaaag gaattttgag tagtgatgaa 33720 agggatgctg aacaggatgc actagtaaat tatgcagaaa tccacctgta caaactattc 33780 aaaggggaag tactcataca aatcagaaaa aaaaatgctt tttgagaatg aaaagaatta 33840 gaagtagttc agagtcagga agataacctg agtaaatcaa aggattgggg cctgaaataa 33900 agtacaatta aataggtctg agagacaata actgacaaca tgcatatata tgcacataaa 33960 ctgtgagagg gtaggaaaca gcaaaagcta tggtaaacat ggaaaggcca ggaaacaact 34020 ttgtggagtt gctctttcct tccatgttta tgtggagtct aggcagagtc ttcaggtcaa 34080 gttttatata gtgagcacct ttacccacta agccatctcc ccaggccaaa aaattgacag 34140 ttctaaagga agtaacaaga aataactagg agatacaaga gtaagaattt tgtttttatc 34200 ggtactgttt tgtactatat aatgacttag aggtaccagg atgatgtcct ggaaacacgg 34260 gtctgatatg atatgagata tgagacccac aaaatatgag gcaagagaaa aaactttggg 34320 ttgaacagga agttcagagg agtacttcta agtacaatca ggagagtatc catacaaggt 34380 gtctatgagt tgggatggaa aagtgagcct ttcaggaagc tgtagcccaa ctctgcaagg 34440 ctctcaaggg ttaaaaacaa gacttcttta ctgtggcaaa tggagactac tagtattatt 34500 gcaagtacat tttcagtgaa atattcctgg attagcagcc tttacatagt gaaatgcagt 34560 acatacatgc actcaaatat tcttacaact gttaccaaag tcaattttct tatttgaaag 34620 tagaagaggg gaaaaaaaaa gggcctctgt ctatattgtg taaacatttt tcctaccaaa 34680 caccaggaac tgttttacac tctaaagatg aaagaagcag caaatggaag ttactattat 34740 tattattatt attattattt tattctggga agggtagaaa ggattaaaat agaccctggg 34800 ataagcagtt aaagaatgaa catcttaaag agtagcctca gtaaaacact tctttctcta 34860 gggtatgtgg attcttgaga aaaaaattct ttaaaagagg ttgatttcag caatagccac 34920 cttatggaaa cacggagtaa tgctgcctag ttgatgcatt tgccacatgt taatgtgaac 34980 aagttctctg aaggctcatt tataggtttc ttttgatata tacattccta cacaggatgt 35040 atttccaaat aaaggtaagg ttattgcaaa tgaatttgat cacacaatta actatagacc 35100 acgatatgta cactcaattt gtttgctgca gctgccaagt ttccagagaa gttttgctgc 35160 aggctgtgct tttatgccat aagtttgaaa tgttctacac tactaaaagg tattttttaa 35220 ctcgtaagta ttgttccatg acaatctagt aaagcaatca tgaaaaggca gccatattaa 35280 tgtggtaaca tgccgagaaa aactgattag gaagcaagtg agagtttttt tttttacctc 35340 tgaaaacttt ttaggatttt tttttcactt tcttttaaat atattgatgt tacttctgtt 35400 tgataatcta tattatcatt tgaaaacttt cacacagata tagtatcaca actacttcaa 35460 tactgtagtg acaataaact gaagaacaca aatctcttca tgaatttatt ttataaaata 35520 tacccactta atttgtcttc ttatcacttt cataatacat aagaagcaca gtggacaaga 35580 tgcccattaa gatgactata gtcacattta gggggtccta taatcaaggt agcatacata 35640 ccacaacagt gttctaaagg ctagctcaga aaaaaaaaaa agaaaacaaa acaaaacaaa 35700 aaaacctcac gttaccttat cacaatatgg aacgcactgt gttctctttt cccattaaaa 35760 tatttaagcc actgtttcat ttagcattac agtaaataag agctctgtct caactactac 35820 aagaaagaaa ataatcctaa gacatccttt tccccttcca atgatttgaa agctaccatt 35880 atcccctgcc aattaaaatc atcaggttga tttgcactag ttgttaaaac aatcaaggca 35940 caagctcaac aggttatctg tagcttgtag taaaatgata taccagtatg tctctcctta 36000 gttaaaaata cataattctt ttattttgtt atgcaacaaa agaaattaac atcacagaca 36060 tagaagacta gggatgggaa actacattaa atatccagta atttaagcct atttgtactt 36120 taatatagga catgaaatct ttaacacctt tgaagtaaat tttaatttgg gggatataca 36180 atttatttct caggagtact agttccattc atttccaggc ctgctaactg tgtaaataag 36240 taacacaagg cacagtagct gtactttctg ttatgctgca acactgatcg agtgccttga 36300 aaaatggttg attaaacaag atgacggcaa cagaagggga gactttggat tgtctattaa 36360 aatctcagca ataataaaga ttcattttaa gtgcactttt acatgcttat ttatacaaca 36420 aacttcctaa ttttgttgca ataggcttga ctatcctatc atttggccag atgcactttc 36480 cccagtaaac ttaaacaaca aaaacaacaa caacaacaaa aacaacaaca acaacaacaa 36540 caacaaaaac aaaaaaaaaa tccctgtcct ttcatatact aagaggattg gctactgaaa 36600 cagttcattg caagacacat gaagacaaca tactgtggca tgagttgttt taatttgttg 36660 tgctgttact aaagttctga gggctgtggt tcaaacattc caagttctcc cttccatctt 36720 tattggttct caaaattttg tacagaaaac tctttggggg ctagaacagc agtacttgca 36780 ccacactgtt tccttgactt caagtttcaa aagcaaattg ttagaaaaaa gttcctgatt 36840 tgacttagat acagggacaa aaaatagcac atacttgaag attacatgtt ctacaaatgg 36900 tggcaatgtt ttccttgcga gaatagtttc gttggtatat atatcttaaa tactcaaaaa 36960 ggctcaacct caagcagtaa taaacacaag caaaagtgat ttaaccctta aaataaatat 37020 tcagaaaacc tctctgtaca tacaagtgaa agaatatgta acactttcac gcaaaaaaat 37080 aattataata ataataaagg atttgttcat atatgcagct gaaatctgct gttccagccc 37140 acaatgtccc caatgaagaa gggaggcaca gacatagatg actactgtgg ttcactatct 37200 tacagccttt ttgtactggg atactattac catcaaatta tccctcttat atttattttt 37260 taactttttc tttttctttt tctttttctt tttgtttaca gcatgccaaa tcctttggca 37320 tatgtgatgg ccttcaacaa tctctcttta agtttttctt tgcttgaata ttccggaagt 37380 aaaaggacat taaagcaagt atgagatgta ggtaacctaa ataaagagaa agggaaaaac 37440 aggacaatca tgagtcattg gaaatatgct cagtgttaaa tgctcctatt agatacatat 37500 cttgttagga cggtttttaa tgagaaacta cagattaaat atatcataaa cattgtactg 37560 tttagttaaa aagatcagtt gggtctttat cctatgaaat aatgcaaaaa ttaaagtgat 37620 gctgatgata gtaacattta ttatctattg agtttccact ctgttaccta ttgctttaga 37680 tactttaaca ctgaagttca tttaaatctt tacacaacaa acatcttact aaacccatta 37740 aaagctgaag tcactaaaca acttacacca aagattaaaa attattcaaa cctggctttt 37800 aaagattttg aagtctatgc tctgtatata gatttgaaat actgctggca aaatgaaaat 37860 gataatgatt gattataaat taattaaaat tagagccaag atgtataaaa tgtctaatta 37920 acagtaataa aaatatatct gtcgatgtat atcgaagtct acctaggaca tattgttcag 37980 ccccaccata aaattgtgaa gtatttattg gagaaagaat acaatcaaaa gtcagaatga 38040 tttaacccta gaataagaat ctagtataat gtaaaagaac agacaatcct ctaaatttta 38100 gtgtagccat tcaaagtaga ctgttctata ataaggcttt cttaataaac tatgaaacaa 38160 agggggaata aaacataaca acttgataac gtctgtactt ctgtaagctc cataattact 38220 ttttaactac actaattttt aaaaaaattc ctcaaatcat gaagggaaaa tatccattcc 38280 actagtgttt gctgacttag atatttcaat ataacatcag aagagtatat agaggctaca 38340 tgttggctct gcttgcgtgt atggaatatg gtgaaaaggt ttacagtggg tacaaagttg 38400 gagtttgata ttacctttct gtgtctgggc catttttggc tataatcatc ttcaattttc 38460 ctagtcctcc aacaggtgct ctgtctgtgc ctgttgtaaa ctgcagaaag agtcttttct 38520 gttcatctgt aaacgaatga acaatttccc agaactccct aatgtgaaaa gagaatactg 38580 gttttaattt gacatccact ataaacaaga tcatagtact acaacattaa ggccaatgtc 38640 acagtgaata ttaaaagtac catttacact tagtatgtaa gttttagtca gccagatttt 38700 atatcttgta ggaactatat atgggataaa tattaataac tcttttgctc agtaattcta 38760 cttaaaaagt acttttgtat tcctaatgct aagcgtgatg ttttaaaatt tacttttgta 38820 aaaaatacat gttcaatatc ctattcacat ttctaaaacc tcaatctaaa aatctatcaa 38880 gatcttctcc aaagcaagag aaatgtgcaa taaatatatc tgtaatctat gctgagaata 38940 aaattggaaa atcaagtaat aaatccccaa agtaaaagta gagagaaata atacacaaga 39000 taagcacagt taaggatcag aataggacaa aaaaattgta gacactggaa gagcggaaga 39060 aagaagtgac gaaactttcc aaagatgata gaaatacctg gtgaagggat tttaattttt 39120 aaaaaattgt aagtgaaaag tagaaggcat tgaatcacat aaagcagaac caaatattaa 39180 agaaacagca gtaaaaggtt ttccttcatt gagaaaccac ttaaagtgac tgtactatgc 39240 tttgctaccc catgacattt actaagagca ggtccatggg aggaaatata taaaaaagta 39300 aatgataaaa aataaattta agtccaatag gaatattatg aagagttctt caaatgagaa 39360 ataaggcttt ttggaatatg aaactatttt taaaaaagac tgagtcgtga ataatataaa 39420 ctctaacatg aaaagtttaa cgatggcatc atgaatcaaa aataaagaga ttaatgaatt 39480 caaacagaaa taataacact tgaaaatact gaggcaggtt ggtgagatgg ctcagcaggt 39540 aggagcacag actgctcttc tgaaggtcct gagttcaaag tcccagcaac ctcatggtgg 39600 ctcacaacca tccgtaatga gatgatccct cttctggcga gtctgaagac agctacagtg 39660 tacttatgta ttataataaa taaatctttt gggccagagt aagcagagtg accggagcga 39720 gcagaggtcc taaaacttca attcccaaca accatgcgaa ggctcacaac catctgttca 39780 gctacagtgt acccatatac ataaaataaa taaataattc ttaaaaagaa aaaagaaaat 39840 tctgaggcaa atgcacatca actctagaaa taaaagatga ttcaaaaatg aggtaagtaa 39900 atgagggaag tgtagtaatt tgtatttgac aaacatccaa catttctact tgacaacagt 39960 ctagaaacaa aaagcaagca aagggttagg aagtcagaag gggaaaggag ttaaaacaaa 40020 atattcaaaa ctgaagaaat gcatatcaaa gtaaaatgga aacaaattgt taattgacta 40080 aaacctttca cttggtaaaa aaccctaaca agtaaagata aatgacatta atgtagagaa 40140 aatactgtaa attactccag agacaaatgt ctctcatgta caagaaaagg caaagggaaa 40200 ggaaatctaa aaagtattcc tatgattcag cattttgaag gttgaggcaa aaggtaggca 40260 agttctaggc taggctatgc tacaagcaag ctattgttca aaagaagggt gtgaggggga 40320 tcaataactg aacaataaaa tgagtaagag acaatattaa aaatatgatt aggtaatata 40380 atgaccttga aaatagaaaa ctatacttca atattatgtg acagctggaa gagagcaaaa 40440 aagttgcaaa gtaacctcta tgttaataag ggattatttt gataatatac ttaaaagatt 40500 ctttctaggt ttgttccttg acaaggcctt accagtcata acattaaata gtaagtctta 40560 ttcctggatg cagttttcta ataatttctt ttaacaatgt tttcttacag ggtaggggat 40620 aatgttcaag ataaggcaaa atttcaaatt ttaacaaagt catgtgtcat gttaaagata 40680 caccaacacc aagcaaagtc ctaagcaagg ctaaagtcct aatggtaaaa cacatttact 40740 acattaaaag taaattcatg agttcataat atctgaaaac aaaaaaatta ccatattatc 40800 tcttcagtat caatcttaaa tatatttgac tttgtctttt caatagattg atatcttaag 40860 gtaacaatat aatagttgat atgaaaaaga taggaaaata ggagaatgac atatgtcaga 40920 tgactagata aaattatttc cttaaatcac catttttata atcacaggtg aaatcatcaa 40980 ttaaggaaag acaaaaaaga tatacaaggc aaaggactat tgatcacagc aattttgtta 41040 ctgctccaca atctctgtaa acagagcaaa tttagatagg aaaatgagag gtcaacaatt 41100 atgttttgtt tattttagtc ttctgaaaag gagacagaat tatttctctt tttaaaaaaa 41160 tgaggaggga gttagaggaa cataaatcag caagcagtgc tgcaatggat cctgctccaa 41220 gtttccttaa tgatggatgg attatgaact ggatgggtat aaaaatgtac aaagccgggc 41280 tggagagatg gctcagcgat taagagcact gactacactt ccaaaggtcc tgagttcaaa 41340 tcccacaaat cacacaacca tgagccacca tgtaaaggaa tgtgatgccc tcttctgatg 41400 tgtctgaaga gaacataaaa atgtacaaag cctcaaatga catagagaaa gtatgaatat 41460 ttcacaaaag aaatgtttct cctcataata agcaagagac tcttctaaga acaaaaagat 41520 tcagtcttga aggtgactaa aatggagaaa gaaaatcaga aaaaaactca aaagaaccga 41580 ggaggaatga ccatgtagaa atgagcagaa tgtgctttta caaaaaaaaa aaaaaaaaaa 41640 aaagaaagaa agaaaagaaa attggacctg agcaaattaa gaatataata cacgagccag 41700 gcgtggtggt gcacgccttt aatcccagca cttgggaggc agatgcaggc agatttctga 41760 gttcgaggcc agcctggtct acccagcaca gccagggata cacagagaaa ccctgtcttg 41820 aaaagcaaca aacaaacaaa caaacaaaag aatataatac acggactgaa gaaccattgc 41880 aacaaggaca ggaatattga ctcaaggtta agaagaaaca tgacatttaa agcaatgtgt 41940 acttttaaag aagctaggga agaacaatct ctaaacagag tcaactataa ctactaactc 42000 cagagattac cagatggcga aaggtaaacg gaggaatctt actaacagga accaagacca 42060 ctcaccatca ccagaaccca gcacacccac ttcgcccagt ccagggaacc ccaacacacc 42120 tgagaaccta gacctagatt taaaagcata tctcatgatg atggtagagg acatcaagaa 42180 ggactttaat aaatcactta aagaaataca ggagaacact gctaaagagt tacaagtcct 42240 taaagaaaaa caggaaaaca caatcaaaca ggtagaagtc cttacagaaa aagaggaaaa 42300 aacatacaaa caggtgatgg aaatgaacaa aaccatacta gacctaaaaa gggaagtaga 42360 cacaataaag aaaactcaaa gcgaggcaac actagagata gaaaccctag gaaagaaatc 42420 tggaaccata gatttgagca tcagcaacag aatacaagag atggaagaga gaatctcagg 42480 tgcagaagat tccatagaga acattggcac aacaatcaaa gaaaatggaa aatgcaaaaa 42540 gatcctaact caaaatatcc aggaaatcca ggacacaata agaagaccaa acgtacggat 42600 aataggagtg gatgagaatg aagattttca actcaaaggt ccagcaaaca tcttcaacaa 42660 aattattgaa gaaaacttcc caaatctaaa gaatgagatg catatgaaca tacaagaagc 42720 ctacagaact ccaaatagac tggaccagaa aagaaattcc tcccgacaca taataatcag 42780 aacatcaaat gcactaaata aagatagaat actaaaagca gtaagggaaa aaggtcaagt 42840 aacatataaa ggcaagccta tcagaattac accagatttt tcaccagaga ctatgaaagc 42900 cagaagagcc tggacagatg ttatacagac actaagagaa cacaaactgc agcccaggct 42960 actataccca gccaaactct caattatcat agagggagaa accaaagtat tccacgacaa 43020 aaccaaattc acgcgttatc tctccacgaa tccagccctt caaaggataa taacagaaaa 43080 aaaccaatac aagaacggga acaacgccct agaaaaaaca agaaggtaat ccctcaacaa 43140 acctaaaaga agacagccac aagaacagaa tgccaccttt aacaactaaa ataacaggaa 43200 gcaacaatta cttttcctta atatctctta acatcaatgg tctcaactcg ccaataaaaa 43260 gacatagact aacaaactgg ctacacaaac aagacccaac attttgctgc ttacaggaaa 43320 ctcatctcag agaaaaagat agacactacc tcagaatgaa aggctggaaa acaattttcc 43380 aagcaaatgg tatgaagaaa caagcaggag tagccatcct aatatctgat aagattgact 43440 tccaacccaa agtcatcaaa aaagacaagg agggacactt cattctcatc aaaggtaaaa 43500 tcctccaaga ggaactctca attctgaata tctatgctcc aaatacaaga gcagccacat 43560 tcactaaaga aactttagta aagctcaaag cacacattgc acctcacaca ataatagtgg 43620 gagacttcaa cacaccactt tcaccaatgg acagatcatg gaaacagaaa ctaaacaggg 43680 acacactgaa actaacagaa gtgatgaaac aaatggatct gacagatatc tacagaacat 43740 tttatcctaa aacaaaagga tataccttct tctcagcacc tcatggtacc ttctccaaaa 43800 ttgaccacat aataggtcac aaatcaggcc tcaacagatt caaaaatatt gaaattgtcc 43860 catgtatcct atcagatcac catgcactaa ggctgatctt caataacaaa ataaataaca 43920 gaaagccaac attcacatgg aaactgaaca acactcttct caatgatacc ttggtcaagg 43980 aaggaataaa gaaagaaatt aaagactttt tagagtttaa tgacaatgaa gccacaacgt 44040 acccaaacct ttgggacaca atgaaagcat ttctaagagg gaaactcata gctatgagtg 44100 ccttcaagaa aaaacgggag agagcacata ctagcagctt gacaacacat ctaaaagctc 44160 tagaaaaaaa ggaagcaaat tcacccaaga ggagtagacg gcaggaaata atcaaactca 44220 ggggtgaaat caaccaagtg gaaacaagaa gaactattca aagaattaac caaacgagga 44280 gttggttctt tgagaaaatc aacaagatag ataaaccctt agctagactc actaaagggc 44340 acagggacaa aatcctaatt aacaaaatca gaaatgaaaa gggagacata acaacagatc 44400 ctgaagaaat ccaaaacacc atcagatcct tctacaaaag gctatactca acaaaactgg 44460 aaaacctgga cgaaatggac aaatttctgg acagatacca ggtaccaaag ttgaatcagg 44520 atcaagttga ccttctaaac agtcccatat cccctaaaga aatagaagca gttattaata 44580 gtctcccagc caaaaaaagc ccaggaccag acgggtttag tgcagagttc tatcagacct 44640 tcaaagaaga tctaactcca gttctgcaca aactttttca caagatagaa gtagaaggta 44700 ttctacccaa ctcattttat gaagccacta ttactctgat acctaaacca cagaaagatc 44760 caacaaagat agagaacttc agaccaattt ctcttatgaa catcgatgca aaaattctta 44820 ataaaattct cgctaaccga atccaagaac acattaaagc aatcatccat cctgaccaag 44880 taggttttat tccagggatg cagggatggt ttaatatacg aaaatccatc aatgtaatcc 44940 attatataaa caaactcaaa gacaaaaacc acatgatcat ctcgttagat gcagaaaaag 45000 catttgacaa gatccaacac ccattcatga taaaagttct ggaaagatca ggaattcaag 45060 gccaatacct aaacatgata aaagcaatct acagcaaacc agtagccaac atcaaagtaa 45120 atggagagaa gctggaagca atcccactaa aatcagggac tagacaaggc tgcccactgt 45180 ctccctacct tttcaacata gtacttgaag tattagccag agcaattcga caacaaaagg 45240 agatcaaggg gatacaaatt ggaaaagagg aagtcaaaat atcacttttt gcagatgata 45300 tgatagtata tataagtgac cctaaaaatt ccaccagaga actcctaaac ctgataaaca 45360 gcttcggtga agtagctgga tataaaatta actcaaacaa gtcaatggcc tttctctaca 45420 caaagaataa acaggctgag aaagaaatta gggaaacaac acccttctca atagccacaa 45480 ataatataaa atatctcggc gtgactctaa cgaaggaagt gaaagatctg tatgataaaa 45540 acttcaagtc cctgaagaaa gaaattaaag aagatctcag aagatggaaa gatctcccat 45600 gctcatggat tggcaggacc aacattgtaa aaatggctat ctagccaaaa gcaatctaca 45660 gattcaatgc aatccccatt aaaattccaa ctcaattctt caacgaatta gaaggagcaa 45720 tttgcaaatt catctggaat aacaaaaaac cgaggatagc aaaaactctt ctcaaggata 45780 aaagaacctc tggtggaatc accatgcctg acctaaagct ttactacaga gcaattgtga 45840 taaaaactgc atggtactgg tatagagaca gacaagtgga ccaatggaat agaattgaag 45900 acccagaaat gaacccacac acctatggtc acttgatctt cgacaaggga gccaaaacca 45960 tccagtggaa gaaagacagc attttcaaca attggtgctg gcacaactgg ttgttatcat 46020 gtagaagaat gcgaatcgat ccatacttat ctccttgtac taaggtcaaa tctaagtgga 46080 tcaaggaact tcacataaaa ccagagacac tgaaacttat agaggagaaa gtggggaaaa 46140 gccttgaaga tatgggcaca ggggaaaaat tcctgaacag aacagcaatg gcttgtactg 46200 taagatcgag aattgacaaa tgggacctaa tgaaactcca aagtttctgc aaggcaaaag 46260 acactgtcta taagacaaaa agaccaccaa cagactggga aaggatcttt acctatccta 46320 aatcagatag gggactaata tccaacatat ataaagaact caagaaggtg gacctcagaa 46380 aatcaaataa cccccttaaa aaatggggct cagaactgaa caaagaattc tcacctgagg 46440 aataccaaat ggcagagaag cacctgaaaa aatgttcaac atccttaatc atcagggaaa 46500 tgcaaatcaa aacaaccctg agattccacc tcacaccagt gagaatggct aagatcaaaa 46560 attcaggtga cagcagatgc tggcgaggat gtggagaaag aggaacactc ctccattgtt 46620 ggtgggattg caggcttgta caaccactct ggaaatcagt ctggcggttc ctcagaaaat 46680 tggacatagt actaccggag gatccagcaa tacctctcct gggcatatat ccagaagaag 46740 ccccaactgg taagaaggac acatgctcca ctatgttcat agcagcctta tttataatag 46800 ccagaaactg gaaagaaccc agatgcccct caacagagga atggatacag aaaatgtggt 46860 acatctacac aatggagtac tactcagcta ttaaaaagaa tgaatttatg aaattcctag 46920 ccaaatggat ggacctggag agcatcatcc tgagtgaggt aacacaatca caaaggaact 46980 cacacaatat gtactcactg ataagtggat actagcccaa aacctaggat acccacgata 47040 taagatacaa tttcctaaac acatgaaact caagaaaaat gaagactgaa gtgtggacac 47100 tatgcccctc cttagaagtg ggaacaaaac acccatggaa ggagttacag aaacaaagta 47160 tggagctgag atgaaaggat ggaccatgta gagactgcca tatccaggga tccaccccat 47220 aatcagcttc caaatgctga caccattgca tacactagca agattttact gaaaggaccc 47280 agatgtagct gtctcttgtg agactatgcc ggggcctagc aaacacagaa gtggatgctc 47340 acagtcagct aatggatgga tcacagggct cccaatggag gagctagaga aagtacccaa 47400 ggagctaaag ggatcttcaa ccctataggt ggaacaacat tatgaactaa ccagtacccc 47460 tgagctcttg actctagctg catatgtatc aaaagatggc ctagtcggcc atcactggaa 47520 agagaggccc attggacacg cagactttgt gtgccccggt acaggggaac gccagggcca 47580 aaggggggga gtgggtgggt aggggagtgg gggtgggtgg gtaaggggga cttttggtaa 47640 agcattggaa atgtaaatga gctaaatacc taataaaaaa tggaaaaaaa aaaaaaataa 47700 agaagctagg acaaaaacta agacaaaaaa tagtaaaaaa gaaagaaaat gaaaaccttt 47760 gaattgaaca gagaatatga agaattaatc acattaaata atggtgattt tattcacact 47820 gataattaaa aaaatttttt gaaagaaaaa aaaaacaaca gttcgttgaa aaagaaatgc 47880 aaaaaagaac agcaaaaagg acagctaata gaccttgaaa caaaaacaaa aaacaaacaa 47940 aacaaaaaca aaaaaaaaag cggaaaactt tcatatagca atggttccag agcatgccag 48000 gaaaagaaaa attaggctcc atttactgat aaaagtgaac atgaaaacct atttgaatga 48060 atagttaaaa aggggatatg gcacaaagaa ctgaagaaca agagttattt ccaataaact 48120 taacttgaac taaaaaagaa ctgaagtagc actacaaaag atgaggagaa agaagggcag 48180 tagcattatg aattactacc ctatgaaaga tgaagagcaa accaaaccag gagctaagta 48240 gttcaacaag ccattataaa aatatccacc aactattcaa gtgccccact tagatttaaa 48300 gtaacaggag atttgaagcc cgaaattaca aggtgattgg tgggagaaat aatgcgggga 48360 ggagaatttg gaggagattg aaagaagctt attggaattt accagaaaat ggaggaaggt 48420 gtgtgtgtgt aaaccaaaca aaaacaaatg ttacctagtt ggttaatagc tcaattttta 48480 ctatagaaag taagaactaa ttgatccctg atcttttaat ctattaacat gttttctccc 48540 aggcatggaa caaatcattt ttctcttttg tagcacacag cagcaggtct tctttccttt 48600 ctccctgtta cttaaagttt cttagtatag acatctattc tgtaaagtgg caaaaaaaaa 48660 gggggggggg gaccagaggt aacacttctt tttttgcttt gttttgttct gttttcttat 48720 gttggcttat ttcctcttta tagaagagga actaaagaac attcttctac aaatgaaaat 48780 gataatcact atgttgcgta gaagttttgt ttgtcaagga tgcaaaattt atttctcttg 48840 tcaaaaccta aaatagactg tggattttcc acgtttatag caattgaaat atatatattt 48900 tgaatgaata attacttgag cttttacatc aaaaattatt ctaacataaa atacaatgta 48960 tttggaactg ttccctttga atggccgatt tttaatagta gtactatgta attttgattg 49020 ttatagtttc aaagtctttc tgaagaagat atagtgatga agtggtctat cattcttttc 49080 atgggaaaga agcatggata agaacaacaa caaaacaaaa aaagccaagg aaagatttta 49140 tttttaaaaa cacgtataat atataatact tacaaatata tgatatgacc ctgatggata 49200 cattataaaa aaaactgtat ctgtactgca tgtagaagcc aagattttca acataataag 49260 gcctcaagat ctaagagaat tagacatagg caaaactgac acaacttttc atttaaaatt 49320 ttagaagtag ggctggaact tattcggtgg ctaaaagcac cagctactat tgcagaggat 49380 ccaggctgga ttcacaaccc ctatatgatg gctcaattcc agtgtcaggg aatccaactc 49440 catcctctag cctcagtgaa cactgcatac acacattgca tagactcaag tatgcaggcc 49500 actcatacaa aaaaaaaata aaatcaaatc aaaaaccaaa gaattgttat ttttaaaagt 49560 atttaattac ctattttcta ttgttgagtt gtttcgtatt ttaattaact gaaagaattt 49620 tattttacag tataaacata tagtaatgtt attttaaaaa ataagaaaca aaaataggaa 49680 tcaaaataaa acacacaatt ttattaaata gtataatcat gaaaactttg tcaatatcaa 49740 caaaagatga aaactataaa gacaagaaaa ttagaaatac atagtaaaaa ctaaaattct 49800 aaaataaagg ctatgaaaac aataactaga tcagaaatga agtttagaaa accttaacag 49860 agaggaacct tgaaaaaatg tgacagaaat aaggttcaat tagaaataaa ttttaaaaat 49920 tataacaaat acaaagaaac tagagataaa ttcaaaacta tacacaacta ggaatataga 49980 caattttaca atcttttaca aacctaaaat agaaagatta aaactatgaa gattcaaaaa 50040 gcaattaagt tgcaccatgg ttcaaatata cagtattaat gggctatggg caaagttctg 50100 ctaggaatag ttgttgccct gaagtgctct cctatccttt gagtcttaga gaccctaggt 50160 aagacaaaga taaccacata ggctgaggta ctgttagaag taccagcaaa aagaagctgg 50220 caagaagcta catgaagtat atattcgcca acatgcaaat agctgaggaa tagttttcct 50280 ctactcaaag acaggaagga gggagggagg gagggaggga gggagggagg gggagagaga 50340 gagagagaga gagagagaga gagagagaga gagagagaga gagtgagtct cactggagaa 50400 acatgccatt cttatgtgtg gggcccatat ccaacagtta gttgaccaac acaatggcat 50460 ctgcagaggt tcttggtctc ataatgttaa ttcatggtgt ttctcccccc catatcttaa 50520 aggtcctctg attatgtatt agagcttcta gttttgtgag ttttgcattt tttatgagat 50580 tctctagtac acaaatatgt gtgtctctac atctatagaa tcatctagaa atttttctct 50640 ttggttcttt ttcttgcttg gctgttgcgt tatcctaatt tgtttgttgt ttgtttatct 50700 ttattattcc ttgatgcttg tttgcttcct tataagagtc agaaaaggca gggagcagat 50760 gggaggggag gtgtaggcaa tctggaaggg gtaggaggac agggaaaaca ataaatatat 50820 tatatggaaa aacaatccat ttttaagaaa gccctcaaaa aataaaacgg aaactatcat 50880 gccaagaaca aagaaattaa aacaactcat gccaacagaa attaaaaaat tgtttgaatt 50940 ttactgacaa ggcttttaaa gcaatgaaag taattataag cttattctca gaaatgaaca 51000 atgaaataat gcataagaaa catattattt aaacttattc actaaagcat acattatttc 51060 aacacaaaaa ttacaaatca atgctggatg aaactatggt ataactaaat ggaaagtgct 51120 atgccatgct tgagatttag aaaatccaaa gtgatgaaaa tgacaattct caaattgatt 51180 tatccaatca attcaaccca aatcaaaaca tcaaaaataa atgttattca tgtaaaattc 51240 agcaaacaga ttttaatatt tacatggaag taaaattagt gaaaacatta agaacaatga 51300 aaaagtaaag ggattctcac catctgatat aaagacttgc tctttgttct atcaaggtaa 51360 aggagtcatc aagatgtgat tttgatcaaa gaacaaatga ataagcagag aagaaccaag 51420 tctagaagta actcacacaa aactcaattt caacaaaaat aaaattcagt gggggaaaga 51480 aagctgcaga ctagaataac acatgtataa catgtttgca tatgatcctt taaaaagaat 51540 acattccaaa agaaatagtt cataatcagt ggaaagaaga gtggggaaga taattcacaa 51600 agtaatggtt aaaaggatgg accatctagt gattgccata tctggggatc caccccataa 51660 tcagcttcca aacgctgaca ccactgcata cactagcaag attttgctga aaggacccag 51720 atgtagctgt ctcttgtgag actatgctgg ggcttagcaa acacagaagt ggatgctcac 51780 agtcagctat tggatggatc acagggctcc caatggagga gctagagaaa gtacccaagg 51840 agctaaaggg atctgcaacc ctataggtgg aacaacatta tgaactaacc agtaccccgg 51900 agttcttgtc tctagctgca tatgtatcaa aagatggcct agtcggccat cactgcaaag 51960 agaggcccat tggacacgca aactgtatat gccccagtac aggggaacgc cagggccaaa 52020 aaaatgagaa tgggtgggta gggaagttga gggggggagg gtatggggga cttttgggat 52080 agcattggaa atgtaattga agaaaatatg taataaaaat attttaaaaa aagataaata 52140 cctaaaagac agctcatgat cctgagtcat cagtgataag caaatttata ctaaggtaaa 52200 attttatttc acactccaag acaacatgac caaagattaa aagagataca gaatacgttc 52260 tagcactgct tgtcatctta ggtaaaatgg cagtatcatt ttacaaaagc attcttgcag 52320 tgcttcttaa ggttaaaaat gttatttact tcacaaccac aatcctccaa agtgcttctt 52380 caggagaaat gaaaacactt caacactaag aatgaaaact ttatttgtaa cagccccact 52440 gtcatgataa ttctattgcc aataacaaaa ggataataat caaaatgcat acattaatca 52500 taatcaatct aaaacattat tttgccatat tgtagagata atactaggat attcccatta 52560 aggcttctgt attaccatgt ttatccctgt tatgaattac ctttaaaact gagcagcaat 52620 ataatggttg ccacttttgt gactggtgtt agaagcaaat atgaatgata aatttttata 52680 ttcattaata attgccattg tgcttagaaa tgatatatca tatgacatgt tatggttttt 52740 gttttgcttt actctgaatt ttgttattta attacctaaa agctgaataa ataacatatt 52800 tgcttttcta ttaaaaaaaa aagggcaaag caagagtaat cttctacaaa cttaaatgaa 52860 taaagtaata ctgtaatata aatataacaa tgataatgta tcattactag acacagttaa 52920 tattcattct attgttaaca tatttgagtc ttatagctca agtgatctac aaaaagataa 52980 ctgtttaaat acctatgaca tcatagtgga tgccaaaaag actactctgc attttgatca 53040 gtcacattag aagatggggg gaaagatctt tcagaattgg atagtagcat attacagaag 53100 tagaaataag ggcatttgac tagagaacga tgttagtggt aatactgtcc taagaattgt 53160 tcagaatcac tagtatacat ggttcttccc aagtatctta aagactaaat aatgtgccat 53220 cttacacatg accaaaaata aggcaaaggg ttgagaaaat atgagactta aatcatttaa 53280 ttcatgaaat aaagcattag actgcatgaa aattggaaat attaatacag gtctattttt 53340 gagcttactt gtttggtaac cagtacctac agatacagga cacaaaagca cacatctaca 53400 tgtttgatga ataaaatctt cctttttaag aattaaacac cttacctaat cacaacagat 53460 tccctcgtat agccaccgtc atactctgta gtttcttcta gtgcctggaa atctagattc 53520 tgaaaattat agggggaaaa aaaagcacct taacatccat agtacaccaa aacaaaaaac 53580 aaaacaaaac acccaaaaca aaaaaaaaaa caaacaaaaa caaacaaaca aaaaaaagac 53640 cttttttgta tatgtctttc ttacccggct tccacatata agcaattcaa tttcttctgg 53700 tctgaataag tattttaagg gcgattcatt agtcaccata tgaaaacctc tgcgaaatgc 53760 cttgaattgt ttttctacag atttattgag aatgtagtct gaatagagat tgacaaattc 53820 ctgtaggaat attaacaaga aagcatattc tatacaaatg aaacacaatt agcttttgga 53880 ctagttttaa tacccaccct ccaccccaag aaaaccttca gcagtatttt ttttgttact 53940 atgtttaaaa attagatttc agagagttgg ttcagtgctt aaaaaagcat tagcaactct 54000 tgaagaataa acataagtct taaaaaatta atcacatgtt atatgtacaa agaaaattat 54060 tttcacaatt tctcacttct gacagatata aaagttgtat tcatatgcat agttatacat 54120 tatgattcta tgagtaaatc aaagagaaat tatataaaat gtaattaata gtaataataa 54180 tgaaataatg taaacagtaa gattaaaata aaagatttaa aaagactgta tatatatata 54240 acaacagaac ctctagtatg caatataaat ttgttatgaa tactgaactt gagaaaacca 54300 gaatgtctca ggtttcctct ggaaattatg gtactggtaa gttagctact gtatccagct 54360 cagcaaaaat gttatttgtt ggtaaactaa gctattataa caaattataa aattttatag 54420 tttttataac tacttcaaac catactaggt aattctttga aaactttaca aattataaaa 54480 tttgttatag tacaaatgta gtttgtatca tgacagtaca atatttcacc aaaaataata 54540 gtataaatta atatatctta aaattatact atgtaatatt ttcttttgaa gctaagttat 54600 ttcctattgc caagtaaata gcttttaaag ttagtaaaaa ccaaatctaa tgtgaataat 54660 ctgatatgca taattagatc tcatgacagt acaatatttc accaaaaata agtataaatt 54720 aatatatttc ttaaaattat actatgtaat attttctttt taagctaagt tatttcctat 54780 tgccaagtaa atagctttta aagttagtaa aaaccaaatc taatgtgaat aatctgatat 54840 gcataattag atctcaaatg gaaaatgtat atacacacta aaccagatgt caatcactgg 54900 gctctgtata cctcttaggt ttaatatggt aaggccctgt ttctagcgtt acattatagt 54960 aatatttacc cattcaatct tttgtagtct gtttagtctt tctctaaagg ggaattaaca 55020 attctgtaca atcacataag ctcttatcta agaggaaagt gtagctttac tatttagata 55080 aatttgttta tgtaaagttt ttataactgc ttcaaaccat actaggtaat tctttgaaaa 55140 ctttactgct ttgaaattat atatttataa aacaatgaca aaaatttaat taccttcctg 55200 ttttcatttg taattggaat tttatcacca ttttctttta gatcatacat cattgggtta 55260 ccaaaaagat ctgtctgtga tatctggaaa gtgatcatca tatcatcttc cacactccct 55320 tcatattcca ataaatcctt taaactctga tataaaacct aacaaccaga aagagaagtg 55380 aggttgccaa ataaatacta aaagaaataa aaataataga ttgttcattc tttgtagaaa 55440 caacttgtca acaaaaatga agccataaat attccacatc tctcaagtag tttaataaga 55500 tagaaaggtt gtcacaggca atgggtcaat cttaaaaatt cttcaaatga tcagttcagc 55560 aacagatttc ataccatggt ctagaatata cactttctct ccatgattgt ggcagggtac 55620 aggaaatgag gaaaaacaaa caaacaaaca aacaaacaaa caggaaaaca aacaacaaaa 55680 aagccacaca catatcaact gtacctatca acaactttac tacatagact catatgggac 55740 attgaaaaca tgatgttttc aacatttttt atggggtcaa tcaaaacata cttgatagga 55800 tatataaaaa atgatgttta ttatacttaa ccagattaaa agtattttac tttactaaac 55860 agcagtatca acaaaagttt acaaataaat aatgttccta tataaactga gataaacttc 55920 tgtatttaga tacaatctta aagactatta acgaaggaca acttactggg tgagagtctc 55980 ccaagtcacg aaaggttcct tttttcccca ttagcttcct gtatacaacc atgggaaaat 56040 ggacatccag tatacaatta ttgtaaatag ccagacccag gactatgcca atcagagtaa 56100 actgaccctc agtttcaaaa gaagatggat taaaccaaaa taatttcgta gcttcatcat 56160 atgtgaacat acctataaag aaataattaa aagtcatttt atccacttaa tgactgaaaa 56220 ttacatatga aacaaatgca tgattaagta aaaaaaaaaa aaacaattgg agaaagttga 56280 ttaactttaa gttacttaaa attcatatca aatctaagct aatataattt taaaaaatat 56340 tttgtgatct ttcagcttca catgatcttc attattcaaa gccaaagtcc agagattttt 56400 tttcctatca tcattatttt atctaggtga acattaagag atagtctttt ttttcttttt 56460 ttacggaaca tcaaacaata aaataaaaca aaactaattg tatatgcctt tcaatttttc 56520 taagtttatt ttcagttgct tctcaggaaa tactttttat acaaagtcta acaagctggg 56580 ggagagagtg ggctgtatac cttagcactt ggtaaaatga gtaaggaaaa ttatgagctt 56640 aaggttagag tactaataca atataaaaag attgtctaaa aaagccaaaa tcaaaatgag 56700 caaatcaaaa agttttggga aatgtttttc taatggaaca agagtattaa aaaacaaata 56760 ataaagcatt aaaatgtact ttcaggttaa ttttaatatt taaaatgttt ccttattttc 56820 actttcagtt ttaattaaaa agaaaagtac acttttctcc ttgaactgta gtaatataaa 56880 ttaagtctaa gctttttctt gcaatttaat atttgtggaa tactggtttc acaagtattc 56940 aattcatact tgcattccag cttgaaaaat gtgagttatg tatgtctgta tcatttgcat 57000 gccaggttat acatccaggt aatatcaaaa gttccagttc acaaataata aatctgatag 57060 aatgtcacca atggatgctc ttggtctcaa ggacaattaa gctataaatt aaccagagga 57120 taaattatat aacctatgat tctcatgact tcaggttttc aaatctacca ctctaaggtt 57180 tttcaaatta aatttcccta gaaggcaact gtgttctact agaatatttg actaagtaat 57240 atatggaaga acctaaatta agtgagtgat agaacagctc ctgaagcagg gatatggcat 57300 actcaatttt tttactgctt accataactg aaaatattta taaaccaagt ttatacttta 57360 aaagactaac acaccatcat aatcatatca ctaatactta ccaatatctg gattaaaaat 57420 ttcctccaca accaactgaa aaaactcttt ggaaacgcct ccctcatcta ctccttgttc 57480 tccttcaaat tccacataca actgcttctt caagtctgca ggattttcca tagcaatcat 57540 ctctagctgt tgattgaaaa tataaaaaag aggacagttg agaagaggaa aaatgtaaga 57600 tataagtaga agaaaataag aagcagcaat aacaaaacaa tatggaaaga aaacaatgaa 57660 ttttgtttct gaaaagaaaa aaagcaaact gacttacagt ttttggcaag atttatttca 57720 acacacaaga gtatgtactg tgtttaagaa gctatgcatt tcttagtaaa ggatatagcc 57780 aaaatgctgt tgggggtggg gtggggggaa tagttgcaat tatgtcctgt atatcttcat 57840 ctttaggggt ctaagggcct atgaatttat tctgtaaaga atctctatat tggtctactt 57900 taactaattt gtatgtcttc atgtatgtat attcacatgt ctccttccac ctaagatgta 57960 tttcctcagg atctgtccac cttgtttgtc aggaaaggat ctctccttga cctggaagac 58020 tgcataacac aataggttgg actgtcaatg gcccctggca tctctgccag tacctgccta 58080 cctagcatca ggactacaat gcccacttca agtttctttt ctttaataga gttctgaaga 58140 ttaaactcag ttcttcttgc aagttgatct accttctcag ctcgcatacc caattttcag 58200 gtcagtattc attgaaattt attttcagca gtactttgtt ggtgaacata taagaaactg 58260 ttctttcaca agttccacat atcaccacta aatattaaca tttaattact aagcttcaat 58320 aaatcaatcc tattttctaa tgtattacag aaacagaggt aatattcttc ctactctaat 58380 ggtatatgct taatatatca tttctaagga gcaaaactgt taacatatta cccttcaaaa 58440 ctatagactt ttaaaattca taaatttatg tccccaagaa attaataggt aggtctgaca 58500 ctttacagcc aaatatatag atttgaattt aaccttagaa atggagaaca aaattatacc 58560 aacaacagca ttagctagaa acctgttcta agacagaata actttgtaca cttaaatttc 58620 catgatcatc ttagctcaaa tttggtccca acacaatata ctattattac tgtggtttct 58680 cccagttctc aacttgctaa gaaaacatgt taattattga ttcaaaggct tgttggtttc 58740 aagacagcat acatctgtcc agtctctacc cttttccccc aattctggtt ctagtatgtt 58800 ctattatgat cactaaaaat aattttctat atttttgctt tcgtttgaaa tgtaaaataa 58860 gcataatgag atagtatcaa ataaataagt gaagtgtgta aattaatgct ctaccattaa 58920 ctctaagttt gaagttgcaa gtattgtcat tctagtaatt tttaaatatt ccatgttttc 58980 tatatatgat agaacaagca tttcatccca gcactcaaac tcggtaagtt tagtgcagtt 59040 atgtctacac agaaaatctg agtccagtga gagctttata gtgattctct atctaaaata 59100 tgataacaag taaataagta tttccagttt tgctagaata tttaaccaca tgattttaaa 59160 aacagaagta ttcccggaat aagagcagca gcagcaacaa attatgaaac ttacagctca 59220 ctttacaatt aaaattgttc tgatatctac aactccttag caagtaggct gctaaaacca 59280 ttttacagaa agtcccttga agtaataaaa ggataaataa cttaagaaat agtaattcag 59340 aagagaagtt ttaatccagg gagcaagctt atagcccaca gtttacctac ttttccaaag 59400 aaaatagaga taatatttgc ttttagattt tgtgtgactt ctttggatat caatattttc 59460 aactatattc acatattatt ttcagaatca ggatatattt gtatataatt taaaaatagt 59520 tggcagctta attctgtaag tgaaaatgtc caactagcaa tttaagaaga ccattctcaa 59580 tgttgccaaa gtgactttgt aaattcttat tttgtttgag atgatgcatc agtagcctgt 59640 ctttttaaaa actatggtaa caaaacaaaa cataaaattt aatactaacc atacacaaaa 59700 gccattagca aagaaagtca cattattttt ttttccttaa atatagtaac tcttgctgag 59760 aggtggtagc acaagccttt aaactcagca ctcaagaggc agaggcaggt ggatctctga 59820 gatctagacc agactagtca acagagcgag caagttccag gacagccagg gctacataaa 59880 ccctctcaaa atacaacccg cccaaaaatg taactcttag aagagacaca cacacaccct 59940 taaaccattg tttcatcaac taaagaatag tataaaaaaa aaaattaaag ttatatttta 60000 aaaatgaatt tgtaaaatca agctgtctta catgtaattg gatacatgaa aactattggg 60060 atatacttaa aattctgaaa aaaatataag acaaaatagg tagtattggc ttcatagata 60120 gcgctggaga aaaaatacac tggtattact atgctgtatt aatgtacaat agtaactatc 60180 acttcctaac tgtacttctc ttcatactag gaaatctcac tctcatcaac tgttaaaata 60240 ttattcttaa tttatttggc aatacaaaat cctagagaga tcatttttta caagctgacc 60300 ttataggaga gcattccaag aaatctaagc agaatgatat actgatttaa aaaaaaaaaa 60360 aaacattcta taaccatatc ttcaaggatc aaaaaaaaat ttagcgccat catttaaaac 60420 ctttagacag ggctggaggg atgatgtatc agcagttaag agcactgact gctctttcaa 60480 gtcctaagtt caattccaag caaacacttg gtggctcaaa gctatctgta ataggatctg 60540 atgctccctt ctgatgtgtc tgaaaataaa taaacatgaa aggaaggaaa caaggaaaga 60600 aggcgggcag gcaggcaggc aggcaggcag gcaggcaggc taaataaaac ctttagacat 60660 ccagagttac catctaaaat cctatgttaa cataactgaa aacaaaaaac tactaatgat 60720 actatttaag ttgaacaaca ctcaaattag ctctatttaa aaatgtttag actctccaag 60780 aagagtaatt tatacacttt gataaaaatc taaatatgac tttcatttct ataagtaaaa 60840 atctctctaa atttctttct tttaaattat tatatgatgc taagctctta tcgtactgac 60900 tacttcatct cccattctgg ttgtaagaaa ttattttgaa gataaaggga agaggattcc 60960 attaatttct tttttttttc tttctttctt tcttcttctt cttttttttt tttttttttt 61020 tttttttttt tttttttaca cgagacaggg tttctctgtg tagcccaggc tatcctgaaa 61080 ctcactctgt agctggcctc gaactcagaa atctgcctgc ctctgcctcc cgagtgctgg 61140 gattaaaggc ttgcgccacc acgcccggct tccattaatt tctattagaa taattttaaa 61200 taagagaaat cacattaagt acaattctat taatgaatga attacaccta gagcagcaca 61260 gaaaaactcc attattaaag caatgtatgt caaatgattt ttttaaatca agttcttgtt 61320 gcaataggta tttatactaa gagaaatgat ggaagctcag ctagacaatg catctagact 61380 ttcagagaaa ttgaggaagt aattcaaaca actttttctt catcgatgtg tgccagctcc 61440 tgggtttttg gacttttctt tccaattcta caacttagca attatttttg gttaactatg 61500 gaaaattcta gaacttaact aaatttattc atgtcccata ccactgtcaa ctcctatttt 61560 agtcacactg acttcattat tcgttttaaa cactggcaat attctacaca tggatattat 61620 tcaataattt atacttataa actgtactaa ctgttgtttc ccaaatattg atttgtagca 61680 tagatgtacc aaaacatgta aagaacagac cactacattt tcatatcaga attctttttt 61740 tttttttttc ctatcagaat tcttagtctg aactcctaaa agtccagacc ttaaattctg 61800 ttgctgtgtt tttattttct gggcaattct gcttttagat tgtgaacgca gtctaaagca 61860 tctcgcacat ggcaatactg tctctggata catctgatct tattccactt tttaaaaaaa 61920 ggttttaaga ttttatatat gctatatcct tgaaatcact ttatttttta aaaagaggag 61980 aaaaatgtgc catttatttg ctggtggtag aagaaaacat gtgccaagga gttaattacg 62040 tcttgtggat taaactcagt catcaagcct ggtggcaagt gactttaccc aataaaccaa 62100 cacaacagcc tacaaagaat atctgttttt tgtttttttt tttttgtttt atttgttttt 62160 tttttttttt aagactgtta aaacttctac actaggattg ttgttcaaat ggaagctggg 62220 atctcattag tatttatatc tgtataattt tctcgttaaa aaaaaaaggc caaaaccatt 62280 caaaataaag caaaagaaat attggagttt tttccttttt agtagaattt gtagatttat 62340 ttctttatta tttatttatt gcttagtaca tacaaatttt aaaaaatagt accttatact 62400 tttatactga ctattctctt gtgagacaga tcttctaaaa ataacagttg ggggaaagag 62460 ttgttatact gattgaaaat aatgaataaa cttttgctta caaaaaagaa ttggctagga 62520 gtgttataca cacataattt tagcactcaa gtggaaaaga taaacaagat cagaagtcca 62580 aggataggct aaacattctt tattaaataa aaataaaaag tgatttccag gacagccagg 62640 gctacacaga gaaaccctgt ctcgaaaaac aaaaaacaaa aacaaacaaa caaacaaaat 62700 taattctaat ttactcgcct actgtctacc attaagccag ctaatctaat taacactgaa 62760 atgtgagatt caatagaaaa cttacaaaag tcacatatgt aatcttttct aggcctcact 62820 tataaactaa ggagaaaacg gtattatttc cttcatagct caaggttagg gttctataac 62880 ctttctttct ttctctctct ctctctctct ctctctctct ctctctcttt ctttctttct 62940 ttctttcttt ctttctttat atttattaat gttgagttca ctgcaaaact tctcattcct 63000 tctctataca accttactat gcagttcaaa atgaccgggt cataaaagat tgtgattaac 63060 atgaatattc tgccaagttt ttttatgaaa gaaagaacaa ggtttcaaaa caatagggat 63120 ttgtggagaa taaagacgtg gaaagagagt agaattccat cagttcatat gtgggtattc 63180 ttttgaatac agcttgctgt aaacctccac ctttttgcta ttaatctaat atgaatataa 63240 taattatcct ttgctcaggg tcatcaattt gatctctaaa gtctgagtct ttgcttctat 63300 ttctaaccct ttcccactag tatgctgaaa aaccaagaaa ttttagaggg gttcagttga 63360 aaatgatcca gaaagagaaa aaaagaggag aagtggaaaa gaaagcaata taggacaaag 63420 aagagctggg tgaaactctt aggaattttc tcaaaaagta cctatctttg taattctact 63480 gcttatcaat gagacaaaca cacagaattg atgaaggcca gggcttctat aaaatactac 63540 tagtcgaata tggatattat caaatgaatc atgtcaaacc atatgactag ttcacataaa 63600 taagatttac tagcaacagt ttgttagcat aattacaaga ctcaactgtt aattttactc 63660 caactacaga aggggctaat ttcgtcctaa atgaaatttt acaaatacta tccaagtttt 63720 aactggttct taactcaata actttattat agaaaaaaat agtataagaa gataataaaa 63780 aaaaaatcag gtaggacagg tgcataaatt ttttattaaa tgtgtattta gctcagtctt 63840 aaggcttttc agatttcgac aatccattcc cccccaaaaa aaataaatgt tcaaataaat 63900 attatttgtt agttatctgt taatgagtta atattatttg ttagactata aggatgatgc 63960 ttcaatctgt aactagtact aaatcttaca tcaagtttat acaagaacta gcactaacag 64020 gaacaattaa taccaaggga taccctgaat tacttatata taattttgtt aatatgtgac 64080 tgacaatttt caaaccaaat ttctggttta actgacaggg actctgtaat ttttgtcgtc 64140 tgtagaaaaa aggaagacaa gaggcaatgt tatttgaaaa caaaaacaaa aatcacgcag 64200 taagaagttc ctgacttccc agttaaatca tctagattta cctggtatta ctaacattaa 64260 ttccaagctc ccaaaatagc cactttacag aattttcaag attcatgtta ttattattta 64320 aaaaaacaaa atcctacaat gtcacacaag acagagtggc ttagaactcc aaagtcttat 64380 tgataataca gactaacctt tcctggtcat atcatcaagt tcacaataga aagctgagtt 64440 gtgttacaca taatggaatt tgaagagcag ctcttattct tttacaatgt acatttattg 64500 cattatttct tccaattcca tcttccattc ttaaaaatgt gtataacaat accatttgtc 64560 atgtgttcca atctttgaaa accaatcttt tcttcttaat ggaaatatat gaggctggct 64620 ttcaagattc agaaaatcca ttccttttac ttgctttgtg cctgtctgtc tgcgcatctg 64680 tgtgcatatg tatgcatgca tgcatgcatg catgtgtgca tgtaaatgcc aaaaggggaa 64740 aacgtatgtg tggaggtcaa agaacatcaa gtatcagact ttgctttcta ccaactgaga 64800 cagggtctag ttatttgtca gtttatatat cagattagct tctgaggatt tttctgtcta 64860 tactttctat cttgctttag gcagtactat tacaaatgga actaccatat cctgttttac 64920 atgtattcag aaaatccaag gataagtcct catgtttgca caacaaacgt tttaaccact 64980 gagtcattcc cctagtacta gaaaaatcta ttcttcttca aaagagaatt atcattagac 65040 aaccaggata ccagtatttt tggtaagaag caacaaaggt gtagcaatac agatcagaaa 65100 tgttaacata atcctatttt tttccaaaat tatagataaa atgaataaat tgaaatacat 65160 cactgtctag gttttagttt aattccaatt ttaaataata gtcaaactta cccggaccag 65220 tgcatcatct ataatatggt cacgtctgac tttgagtctc aaatacggat tcaactgctg 65280 tccttgaact aggctgtaaa gaacagtgat tcttctttca ctgtacatgc gaattctatt 65340 gtcataatat aatcccagat tctttgtgac agcattcaat ataaagggac atgtcataaa 65400 agagaatttg ttctctgttt caactttgaa aaaggtataa tctttgtcca tttctagaac 65460 atcattcagt ggttcattaa tgaattcttc aaaggagata agtggttttc gacagtctag 65520 agttttaacg ccaagttcgg tttctagtgg atccactcga ggacctttct tatttcttct 65580 ttcatctccc agaagctcct gaagtgttaa ttcgctggac tcaggtatgg gttcttcatc 65640 atcttcctca ttatgatttg tgtccacatc ccctcccact acatttgcat agtaaaccat 65700 tttcaaacac tttgaagcag caacaatggc atcatcatca ttcactagat ttcggctatt 65760 aaattcattg cttatgactt tgtaggtaat aagttgctga aatgtttcca tcattctccg 65820 aatctggtca gcactgtatt tagaccacag cctaatcagt tttccttgag cttcaagggg 65880 tagcttacac atagctttgc aaaataatgg caacgccatt tccagatatt caggactgtg 65940 gagattacta ttctccatta caataatgaa caaattgaga taattaggat ctcgagtata 66000 cacattatga tatgtcaaat cacattccac gttaggtgac agatatacaa gtgcattcag 66060 gaaggcagtt tctaattttt cattagcgag caaactgctg tagacccttc taatagcatc 66120 aatatccaca gtcacatcat caggacctaa tttttgtaca ttgttgtctc cctgtgaact 66180 atcacccatc cttgaagaag atgcttctga gtcttcttcc atagcagcag cagaacatgc 66240 agctttttcc ttttcatctt catccttgtc ttcatccttt tcttgaagag atttcaattc 66300 ctcctttgtg tgctgtttga ctttccgaaa gctcagaacc agtgcctcag cactagaaaa 66360 tattcttcca attacacgaa ttaaagggga ataatcctca ctctctctac aaaattcata 66420 aatttcatat actttctctt cagttaggta aatcacatct agaaaatgga aagaaaaaga 66480 acatttatgt tgtaatatac atgtttattt tgttaaaata attgctagtg aaaaagtaaa 66540 atatctaaac attctggact tgatttagaa tttttaaatg atgtaattta cttattaaca 66600 agtaatccca acaatctcac cctttcttgg cattcattga acaaaatata attattaatt 66660 atgcattgat aattaagaca tgccttgtaa ccaagacatg tactggtatg taacattaat 66720 tgtaggtatg aacaaatata tatacttgtc atttcctcat tgtactttat tacaacctta 66780 acaaaaagct actatataaa atcctgaaat cattttcctt tgcattgttc tcaaaaaact 66840 aaggaggtaa ggttttataa caaggtttcc ttagcccctt catttgcaat caactctttc 66900 tatacttttg tatatactaa aaccaaactg actcatctta tgtattccta atttcttcca 66960 gaatttccat tcagaggctg aggaaaagat attactactc atgtaaactc tactgaagtt 67020 aaaactgcta ctacaactac tactacctat gaccattact caggttctaa caattcttaa 67080 cagagcaact ggaaattatt acagtcatca gtcatttaaa aacaaacaga agaaagaagc 67140 taagaaagca aaaaccacaa gcactaaaac ctatatttat tttctcccag aaatagaatt 67200 gggatcataa aagtctctag cttctcacca ctaggccaaa tgtaaatttc aacaaaggct 67260 ttaccatttc aggttaacaa aacaaaagat acttatcttt ttggaaaaag gtaacatttt 67320 acatattaaa gttttagaaa gtaatatatt tatcaaataa taatgttgaa accactaatc 67380 tctttcacca aagagtaaca tattataatt attaaacatt taagttagga taattttatg 67440 gttacattga taatacacct catacattgc caatatatct aacatgtaaa atctttatta 67500 tgattgctac atattattaa aggtacctaa ttcaaaaata agaaacaata taaaattcaa 67560 gtcctcattg atggaatggc ttccaaaaca taaaccacaa agcactaaac tatatatact 67620 acaaacctgt ctatggccca ttctagagta ttgatacttt ttaattttat gatcttcaat 67680 tctttctttt aaaaaaatgt tctatttact tattagaggt gatgagggta ttgagctgag 67740 ttgataacct aaaagaatta attttctcct tctacagtgt gagtttcagt agttacatgt 67800 ccctatctga ggcagcatgg caagccaagt tcaattctta gtctactaag aataagtaaa 67860 aaagaaaaca ctaacatgga gctcatttct cgttattcta actgaaaaaa atacatggaa 67920 tcttctttaa ccattcaagt ctaccaaatt tctctaaact gtaaccaaaa cacagaaaat 67980 atcagtaatg aataaatagg cagactgtta gaatataatg ttttatctcc ctatcattga 68040 attataaaat tagttagaaa gtgcaaattc tacatacaga acaatataca tcctgcctga 68100 aagagaataa agctctagat ccacacacct ttgatttgca atgtcttcct ttcagagcac 68160 agtcattaaa tcactctgac attctagtaa tacaaactac tattcattga tatttgttcc 68220 acgtagtact ctacttaaaa tgtttaaaat gtttatctcc atctccccca cccctctcat 68280 gtgtgcatat aaatcactgc aatcagaaat aaaaagttct aatctgggta tcaacaaaca 68340 gttaagtaaa gaaacttttt ttttttaaga ttcacctgta cattctaata tatgtgtgct 68400 tgaaaactgt ttgagacatg gtttcacata gtagaaacag aactggaaat cagctcaaaa 68460 tctttaaaac ataacatttt atactccaaa cagtttcacg caaaaacaga gttgtgatac 68520 actagctgat aactacacct ctaactaaag tgaacaaata taattatcaa actgagggaa 68580 acatgattaa gcatatataa ttcaaaaata ttaaagaagt aaaggcaata aaatttggag 68640 tgatccacaa aaacaaagaa cctgtaaaaa aggaacaccc atgggctaaa acaaggcaac 68700 tatatccatt atatactaga tttttcccac agttagttgc attcaactat gatgggatac 68760 tatttttcat ttactgttac tctgtcatgt ccactctgtt gtagaaacat gtataattga 68820 gccaatgcaa ttttcacatt caaaatattg attagcattc acctacttat ctacaatgta 68880 aacaaattca tgaaatagga ctggctatat atttttgagt agcaaagctg aaagtttttt 68940 tttctgattt ttctttagtc ctattgtgaa agtaatatca tgaagttgta ctataatttt 69000 atttcactaa ttcatttaaa catgtttcaa gtgatagtgg aactaatccc tggcaatctg 69060 aaacattcaa ttacttccat taagagaaaa aaatagattg aacaaaatca atcatgaggc 69120 aaagtaggaa atttgaagaa ttttcaaaat atagaactat ttttaaaata ctagatgcat 69180 tggggacata gcttaatcgt gagtgcttat ttttcactca tgaggctatc ctcagtacca 69240 ggtatcagag tataaaactt taatttcatt actggggaaa tagaagtgtg agtattaaaa 69300 gtacaagaat agtgccactt aacttgcaca aaacaaaatg aaacgaaacc ccacaagagc 69360 tgagtaaaga ctattactgg taagttacgt ccctaagcag tatgaaaata tctaattcct 69420 gacgtagaga gggcagaatg taagaaggaa aaaatgtaat tttcagataa ctattgcaaa 69480 attttaccct gctttcttaa aaaaagaaaa gaaaaaaaaa aaaagactac tttacacttt 69540 atatttgtat ttctcctttt accacagtcc ctggagttct agagccgata ctaggtattc 69600 acggcaaatg caatgtacat agtagatttt tgtgacctaa taaggtatta gctacaatat 69660 aaatcattac aaactgagtt caactcatca tcatattaat ttttagagta taacttgctt 69720 ctgactgaca actaatgaat cagtaaaata taagaataaa atgtaaacaa actaaatacc 69780 agtcctttac cacagtttac cagaaaaggt gacttttact atattatagt gcgataactt 69840 aaggtgataa aaaaagcaaa aacaaaaata aaaacaaaat aacaacaaca aacaaaaaaa 69900 caaaatcaaa acaaataaac aaccccctcc acatttaaat ctgatatagc tttcaattaa 69960 ccattttgaa ttgaaatata atctcttacc tttaaaatct tttccttcct tcttgttcat 70020 ttttatctct gagttgttag atgcaccttt tgagttctca aggtaagctg agcttgctcc 70080 tttcttggag ggatgaggat cacagagttt tgcattaatt ttataaagct caagggcttt 70140 aatagctgct gcattgttat ccatacgaag aaaagttgga caggaagcac aaaactcatt 70200 cgtgcaggcc tcatttccac agccctcagt taactgatgg tagtagcgtt ctattagatg 70260 ctttgcagct gctcgcttcc tgtaccagac attcaaacaa taagcacatt tattagtata 70320 gctcagaaac aaagcccaac agataaggca aaagttagct aagcaataaa gcaataaact 70380 aaatatttag atgtagaaac tggaaattca ctactacctc ccaaagtgtt agtaaaataa 70440 taaacatttt ctaaaaaaac tgtgataaac tatgtcagct tataagataa ttttaatatg 70500 gcaggctttt ctttggttta aaaaaagata agcttaagtt gatggtatag gacccttaac 70560 tatttagcag aaaacaacaa aaacaaactt cactgctaca tctccatggc agtttccctt 70620 ttcactaata taaaatcact aattcatttt aacagtttca aatacttgat ttccagttaa 70680 tatcaaactt ctagagatta aaatttttta ctcagtaagt aatcatgaga tatttaaaag 70740 tgctttataa ataaactatc taatttcata ttataccgag agagaagcac caaggcatac 70800 aaccttgagc ccatacttgt cactatcttc attaaatcct tgtcatagga aagataaagg 70860 tttaaacttc catcagggga aactcatatt catcttactt catcaacttt aaacattaaa 70920 attaacattt gattaacata tttttcatgc aaagtaacca atacaattaa aggaatgaat 70980 tattttacca aacaagaagt tgttctacat aacctaaatt ctataatttg actctaaaat 71040 tctattcttg gagattacca caaaatttaa gttgaaatgt atatctggcc cataataatg 71100 tcattctaag gaatccgttt ggttctatac aagcatggga actgcaagta gaaagaatct 71160 atctaatttc attctaaaac ttcatgtcat tattttagat agaactaagt gactaatggc 71220 actagagata aacaaatatg gcactgataa gtgactttag gactatgtca ttctttgtat 71280 gacaaagaat ggtatgtcat acgatcctaa ctcattcaga tacttatatt tagaaatatt 71340 ccctgtatat ttaccatgca tagtgtacaa aggccaagcc tgatgactca agtttgatcc 71400 ctgtatccaa cttggtgaaa ggagagaact aattaccaca agttgtcctc tgaactctaa 71460 acacaccaaa acatatgccc agtcacatgt atctacagaa aataaataaa tgtgatgaag 71520 tttaaaatgt atcacgaagt tagagatacc acttatgaga aaaattcatc aaaaggaaga 71580 cttatttccc tattatttat ggaaactcag catgcttaac aacagcaaac cgcttcaata 71640 tactgacagc atgcaccaaa taaaataatt accaactact ttaattttgt tacttcctta 71700 acaaaagcta gtgatcaagt tataaatgta ggatgaatgt ttcgaaatat taactatttt 71760 tctaaataat tgactgagtt aattcttcct agctacgttt tttctgtaag tatgtaccta 71820 aacactaaaa atttctaagt atcagtacgg aagttttaaa acttcatcta cgtgatttaa 71880 atagagccaa tgtttatgtt tatatccagg atttttaagc gttaatttca aagttcaaaa 71940 cactagtttt ctaagagtac taggccgccc ccccaaccca tacacacaca cacacacata 72000 cacacactac ttctttatgt gataaagaac tctcaatact gaagggagaa atgagaccat 72060 ccaaaagtca gctcaatgta attagttgaa tgaactaatt ttctaggcct cattttacca 72120 ccttatgtcc ttataatttg tctagctagc actctctaca tgccaaataa taaactcagt 72180 acattgtcag gtactctgat tatcatatga aacttgaact tgaagattat cttctgtcta 72240 cagctagtaa aagagaaaga cctgaaaaga tcaaatctta taattgatct tatgctatgt 72300 ccattaaaga agtcaggaca attttcagct tcagaattca atttatttcc aatcactgtt 72360 ttacagatta taatttcaga agaattaatt cttaatacca gcagtcctaa aaagttttaa 72420 gggggaaaaa aagacctaag taatatataa ttagaaaaca aaatcttcca aaaaattcca 72480 atctaaactt aacaaccatg tgtactatct gggtacagta tagaaactcc tgaataaatt 72540 atatcactat acttaagata tcggtaattt attgaaaatg gatatgctaa gcactttata 72600 agaagactca gtctgtaaca ggtagaaatt cacaattttg aggccagatt gtttgggttc 72660 atgaacagtt tctgtatctg agttaactac ttatttagtc tctttctgtg tctcagcttc 72720 ctcatcctta ggatgccagt atatttcaga attcaaatga tttaagaatt acaagtgttt 72780 agactatttc agtaaatttt ggaagaggta ggaaaaaaat aggaggtgaa gatgagcaaa 72840 atgcattgta tcatatatga aatcctcaat taatggaata gtatgtatta cctgctacat 72900 gctaggccct aatggtaagt atcagatgct attgcaattg ctataatttc tatcatttgc 72960 atgagtatat gacttggtca agagaactcc attgcactaa atctgaaaaa ttaaaatcta 73020 ggcttaattc caaaatttga aattttagca ttactaaagg ggagacagca gagaaaatgt 73080 ttgaaactga ccagcttttt tgcaccaagt tacaagtagt agcccactaa tactaataat 73140 tatattaaat taaataaaca gaggtcataa tcaaccatat taagttgact aatttgatta 73200 atgtgcgttt attaatatta agttaattaa attggttaat atgattgaat atgattaatt 73260 aacaataata agctattctt ttctcattat aaatgatacc attgaatgcc aaatgcaggg 73320 catataaatt cattaaggac atgtaaaagg cctctaaagt tggaaacata catactaata 73380 atagcttttg ataaccttcc aatgctaatc catacatagg actggtcact aaatcatacc 73440 tcatgtgtca aatctacttt ttttacagtt gaagtttaga atattttata gtcttaaatc 73500 attaaaaaat tatattttgt ttcatgtgtg aaaattgcat aaaacttaaa tgtctatgtc 73560 cataatttct aatgtaacat ggtaaatttc aagtacttgt atatttcctg tatgttctct 73620 atcataatgt atctagccaa aagtaaaatg ctttgtcacc ttaaaatgaa ttccctgtgc 73680 atgccagtga aactttcaac caatcatctg gcctccttac tttctctctt tgtcctcaga 73740 agatgaatag agtaaggttc tttcttccta cttagtactt taacaaaaag ggagtgggga 73800 agtaggaagg aacataaaag aaaaaccaaa gtaaagttca ggaaatgaag tgaatccgtt 73860 tcctgatatt cataaccaaa actctacaaa aaggaggtag cagttacttt tgcctattca 73920 tattccactg acttcgtgga aatcaaagta caatatagtg agtccttaaa taaaaatatg 73980 ccttttttat ttagtttata agaatcaagt gaatcctacc agtaaaagtg ttcctcttta 74040 aataatagtt tccacttctt tattactttc taagaagcca ttaaaacgga ttctacggaa 74100 actgatagaa gcagatgcag ggacccacag ccaaaccctt gaagagtcct gctgaagagg 74160 ggaagggagc caaaggacac cacaaaaaca tagcccacag aatcaactca gcagggctca 74220 taaggggtta acagagactg aagcaacaat tggggagtct gacctgggtc ttctgcatat 74280 gttatagttt tgtatagctt gatgtccttg tgtgacaatt agcagtgaaa gtaagggatg 74340 tctccgactc tcctgcctgc ttttgagaac tttatcctcc caatggcttg ccttgtccac 74400 cctcaatggg aaggttatgt gtgtgcctaa tcttattgaa acttgttgtt atgccaggtt 74460 tggttgatat tcatgggaag cctgctcttt aatgacggga aagaagaggg tagtggatct 74520 gaagcatgag ggaagggagg aggaaagaac tgagaggagt gcagggagaa gaaaatgcag 74580 acaggataaa ctatatgaaa gaattaatta ataactaatt gatgttttcc acaaatgaca 74640 ataaagagaa ataattttca gtgttctcag tagcactaat aacattattt gctgggtcct 74700 aagttaattt cgggatagtt gaatacttag gaatagtaag taaatcataa taaaaatgat 74760 aaagttataa gatattcata actatatata gatagcatca aggagattat acactagaag 74820 aataaagaat tcccacatag ttcagcatga gaatcaaaaa cagtgaaata gctgccatga 74880 aaacaagaaa cagaaacatg aaagagataa ctaacaatat gacttattca aagtatcttt 74940 tttaaaaaaa taagcagaat aaaaacaaag attggacaaa agaggtaaga aacatataca 75000 gcccaagact caattaaccc atgcataatc tagtaagcac tgcttagtgt ctttcatagg 75060 taaatgtctc attattttgt aaggggtttt ataaaggatg tacctttata aaaatcacta 75120 ctcctccaag aaatggtggc ttatgcttat aatagtagca tatactagac taaggcagga 75180 agatcttgag tttattatga actttatgtg gaggaatcag taaaccaaat ttcacaactt 75240 gccccaagtt atttttaatg tagaaacttg tcaagagtaa aaaatgtgat ctcacaaaca 75300 ccagagatat tcataataca gttaaaacca gtataaggta gggtctattg aagtgtcatc 75360 aaatcatgta ttacaagact gaaagtacaa atatgaccca attagtatca ggaaccattt 75420 gaaagtcaat tatatataaa ataaggaaaa tttcttaaag acagatagat gggtggatgg 75480 atggatacta aaaatgcttt tattcatctt tacaacaaag tactagttgt aaaaatagaa 75540 ctgtggaatt aaattttcac atagaattat ttatctttta aaatgaataa accactgttt 75600 ttggggtttt ttttttgttt gtttgtttgt ttttcacctg cccagtttca tggttagaag 75660 aaagtaagta aacatttaca aatttagaaa ttgactagtg gagctggaaa catagtgtag 75720 tagaggcaca ccaccaatat atattgtata aatatataaa actttcaaag aatattattt 75780 tttaaacaaa gatcttttcc taaaaccata ggttgactct tctttctgta aacagaaggt 75840 gaatattggc tgattgtagt gaatgctagt tttagaactt gtatatttcc taagtaagaa 75900 ttttgaaaat ggaaatctgt cctgtattag tttggaaaga gttagtacca ctgccataca 75960 aacagcagat acctgatagg agactagagt gatggctcac tagtcaaaag cactagctgc 76020 tttttcagag gaacagagtt cagttcctag catgatgtca ggtggctcac aaaactgcct 76080 gttcctccag cttaagagca ttaaatgcca caggcaccca cacacatata gcatgcatat 76140 gcatatatgc atatatatat atatataaat atatatatat atatatatat atacacacac 76200 atatacatat acacatatta aatctaaata cagtcaaaac caatgcacaa aacacatttg 76260 aaaaagaaca catgtccttg ctaaaatccc attacttaaa agaaatcttg tgaagccaaa 76320 aggctttcag acagactcat ttgagaacat gaataaccac tcccagtgat agagatatct 76380 cagtagttaa gagcactgat tcctcctctt ccaaggaatc cagatttgat tctccacacc 76440 aacaaactgg tgcagtcagc tgtgacacct ggaggagtta cacactcatc tggtctccat 76500 gggcaccgac catgctacat gtggtgcaca gagatatatc ccagcaaacc acagataaac 76560 ataaaaagga ggaggaagag gaagaagaaa tggaggagga gaaatattta ctcttaccac 76620 ctctaatgga tgaagtacaa tatctaggca tagctatcag ataagaaaaa gataaaagat 76680 acaggaacat ttggaataag atgcaagact acaaggtgct aatgtgataa agtgaatgaa 76740 aacttccaga gtatcaaagg ataaattcaa attctaagag agatgaagaa tattggaaat 76800 cacaaaagag atactacaac tgagaaacag agaaaaatac tatgtagcaa aaaggaaaag 76860 cagcaagtgg ctccagccaa gtggtggtga taagggatat ctcatccata aggtaaaaca 76920 gatgggactg actaaaacaa tgcaatagtc ttgatcacag aacaagcaag agtactcaca 76980 aagaattaat tggaggtttc gtcatgacac tgacttattc taagtcagca ctggaaaggg 77040 aaaaatccag tttataactg tattctggag aactagtcag gtgtcatgaa aagggatcta 77100 catttgtttg aaaacaaaca atcttggggg ttgaaaaaca tgaaacaatt acaaataagg 77160 aaaaggggtg aagtcttgcc atagtctatg ggtgggaaga aagctgagtc aggtagatat 77220 ggagtagaga cttgattgac tgagaaactc aagcaaagta gacaaggctt gaagggcact 77280 gtgtcaatta accagccctt ctgtggcaag gatcaaaccc tacaatgtgg aggataaagt 77340 gtcaagccta caaaattggc tctgtctgtc atgagggttg ctgcctacag tacttgacaa 77400 ctctgaaggt aaggtccagt ggagaaattg attccagctg tctgataccc cttgcaatgt 77460 ggtgacgaca ggcaggatct aaaagtatag agaccagttc tctagaacaa acagtgcttt 77520 tttgacttcc ctcatttaaa gcatacttgg gagacaccct gtggcttgaa agtagccaac 77580 taagacagaa aagctggaaa gtccctgaag gaaataatga atgagtgaat gaatgaatac 77640 ataaataaat aggtgaaaat ttaaaaaata aatgtaaaaa tccctaggtc ctgtacagca 77700 aagttcagct agcaaagaca ctggtattca aaaacactga caatctcaaa ccgaagatag 77760 ttttctatga catctgagct ttgactggtt ccaaatcagc accagcctca ataacaggac 77820 tggaatatta ggggatgcag aataaattac tccaatacac ttccttttac ttgttattgt 77880 tttagacttt attttttgta agactattat ttacttacta ttctatttat ttgtttgctt 77940 tctattttgt ttgctttctt tacttattga ccatttgttc cattcccatt attcttagta 78000 ttctacttct tttcatttaa acttgcttcc cttttctttt cctgcccctt tccccttttt 78060 tttttcctta agctgctatt tctaatttga ccctaaacaa gttttgacta cttacattat 78120 tctaaacata tttttaatta tcaatggtgc tataaatgct ggcatcaatc aattcaaagt 78180 ctatatctga aaattgtttg gttttattgt atgtgttgga ggtttctttc ctcctttgag 78240 tagtgttaag gattgaaaac tcaacagaag gctaattaca aataaaactg gaaaacatat 78300 ccatactgac aagtgtacaa attagaacac aaaaacaaac aaaacattat aaatggaaca 78360 aagttatttc agaagatcag catttaataa ccaataaaaa gatggccaac tgtttgaaat 78420 gctgttcaaa gaattctgaa gtacatgtca atgagaagtt tagcaaagaa attgagactg 78480 gtgctgggag ggaggatgat ggaaataaat aaaataatta aaaatctcag tggaaaccat 78540 aaataataga ccaaatcaag tacaagacag aacagcagga attgaagaaa aatctgtatt 78600 cagacacaca acaacacaat aagtaaacac aaccaaacct tttagaacat gatcaaaatg 78660 aaactaaaga atacatggag cagaaggaac ttaaaagcac tgagactaag tcaatgaaat 78720 aacagcagaa attttctaaa atatcgagaa agaaatgaac atctatacag aaagatgtgt 78780 aaaacccaaa taaatcatgg acagaaagaa ttgctcctga gcacagtgta gctcaaatcc 78840 taacactaca aagaaaataa aagtatcaac atactaacaa aggtaaattc actgtaacat 78900 ccaacctctc actagaaatt tttaaagaca aaaatctttt caatgattac tatatccaaa 78960 gttatctttt aaatgtaata taaaaacttt ccaaggtagg cataacataa ggccacttgt 79020 gaccactaaa ctacagtata cacttaaagg aaacttacac atagcagaat gatacaaaca 79080 gaggagctca aggaaaatga attttgtaat tctatatatg aaaaattaag aaagaagcaa 79140 ctgtgtctac ataagttaat gaaagaaaaa cagaacaatg aaagaaacaa caaaatataa 79200 atgtttttag cgttccattt atgagacaga ttagccaaat gaattaaaag caggatcaaa 79260 ttatttgttg tctataagaa atgtatttca cttgaacaga agctaaagga aaaaaaaaag 79320 gagactgaaa agtgagtgga aatcaaaaaa gaactggact actgacataa gtatatgact 79380 gtatactata aaagaaaaca actgggctgg agagatagct cagcggttaa aagcacctac 79440 tgctcttcca aaggtcccga gttcaaattc cagcaaccac agggtggctc acaaccatct 79500 gtaatgagat ctgacactct cttctggtgt gtctgatgac agctacagtg tacttacata 79560 taataataaa taaatctctt taaaaatata ttaaaaatgt aattgaggaa aatacctaaa 79620 aaaatatttt aaaaaatatt taaaaaaaga aaacaaccaa tgagggatgt acaattaatt 79680 ataagtatat atgcattaaa tgatggtgta cccaagttca taaaaacaag cactaccaga 79740 ctactgtaaa atccaacctc tcgggctggt gagatggctc agtgggtaag agcacccgac 79800 tgctcttccg aaggtcccga gttcaaatcc cagcaaccac atggtggctc acaaccatct 79860 gtaacaagat ctgacgccct cttctggtct gtctgaagac agctgcagtg tacttacata 79920 taataaataa ataaatctta aaaaaaaatc caacctctca ccagaaagta caatatccat 79980 atagaaagta acaagtcaaa atacagtaaa atacagtaat aatcttaact ttccaaatta 80040 ataacttatc tgatggaaag aaggaaggaa ggaaggaagg aaggaaggaa ggaaggaaga 80100 ttgattttat ctaaactgta ccaaacatca aatggactta tttcaagaca tctaaaaaac 80160 atctcacctt ctgcagaata aaccttggca gcccatggaa ctctctaaga gataaaccac 80220 atttttgaac attaggcaag tcaacaatag taaaaattac tttcttgtac ttaacaaata 80280 ataagagaat aaaattaaaa tgcaaaaaaa aaactaggta tgctacaaat acctgaagac 80340 aatataatac aatcttaagt atcataagag taactgaagg aatcagaaca gaagtgtttt 80400 aaaggaataa gtcaaatgaa aagaaaacac actaggaaac agcaaaatca tcctcagtga 80460 agtaactcag actcagacag ataaatatgg tatgtattca cttataaaaa aaaaggatat 80520 tagcagttaa gtaaataata accaaggtac aatctataga gccagagagg ttaggtaaag 80580 aggggggatc cagtagggat acaaggatct ccctagaaga gtgaaataga ttatacagcc 80640 aactgggagt agatagggag agtaagcagg tgtggggagg tgagcaggtg gagggagaga 80700 tggggttgag ggaaagtgtg gtagaaacag ctggaattgg ggaggaaaga atttccatgt 80760 tggtgtagaa acctagtgca ttggaaatgt ccttgaatgt atgaaagtga ccctaataaa 80820 atggtctagt aatggaagat atagaatctt aagtggccat ctcttgtctc cagacaacca 80880 aagtgagttg cacttcagtt aagtgaagag ggtcccatag aaattcccaa acagggctgg 80940 aaagatggct cagcagttaa gaccactgac tgctcttcca gaggtcctaa gctcaatccc 81000 cagcaaccat atggtggctc acaaccatct gtaataggat ccaatgccct cttctggtgt 81060 gtctgaagac agcaacagtg tacccactta tatgaaataa ataaatctta gaagaaggag 81120 gaggaggagg aggaagaggg agaaaagaga agaggaggag gaggaggagg aggaggagga 81180 ggaggaggag gaggaggagg aggaggagga gaagaagaag aagaagaaga agaagaagaa 81240 gaagaagaag aagaagaaga agaagaagaa gaagaagaag acgacaagaa agaaagaaag 81300 aaagaaagaa agaaagaaag aaagaaagaa agaaagaaag aaagaaagaa agaataatcc 81360 ccaaacagcc taagctgttg tcaaaacaac aggttgctac ctgaaaacta acagtagagc 81420 cctactgcta aggacaatat ccacactacc caatgaacac ggagaagcca agctgctgcc 81480 tgcatggact cttcacccct acactctact tctttggtgt aggaaggtac tctacaagct 81540 accaaaagag atatacgcac accaacccag ccacaaaacc tttgacctac aatctgtcct 81600 tcctgtaaaa tatgctaagg cagtaggggc aaagaactag tgggagtagc caaccaatgt 81660 ctgatttgac ttaaggccca ctccatgaga agaagcctat atccagactg cttggataac 81720 taagaaccag aaacctaggg taaaacaaaa acactactta cgttttaaat ttttttttta 81780 aatcttaaaa aattttaaag tcaataaaat gattatggta tacacattgt atcagtgcct 81840 aatctagtta ctgtcaaaag aggttttctc tggcagcaga tggaaacagg tgcagagatg 81900 gagagaccac agtcagacat tacatggaca gaatatttaa atgggagctc tcaatcaaat 81960 actttacagc agagagcagg gaagcccttg gaagagaagg tggaaaaact ttaagagcca 82020 gaggggatgg acgataccag aacaagaccc tctaaatcaa ctacgaaagt ctcataggaa 82080 atgtcataaa ctgaagcagt gggtctgtac caggtatgta tgtctgtatg tatgtctgta 82140 tgtatttgta agtgtctgtg tgtattatat atgtatgtat gtatgcatgt atatgtatgc 82200 atatacatac atacatgtac tacatgtatt acatatatta cgtgtattac atatatatgt 82260 agtatattta tactacaaat atgtatatac atataataca cacacacata ggcacacacg 82320 catgtgcaca caaacacaca tgtaaaatag ctataggttt agtattgtat ggtactccct 82380 ggtgtgagaa cgaattaggc ttctgactct tatgcctgct cttgtgactc ttttcctctt 82440 gtttaccaag gcagactacc atgatagttt ttgcttcatc ttattgtatt ttattttgtc 82500 atgttaaaaa aaaaatcaag aaaggaaaat atattatgat acagaaaggc atctctaaca 82560 gtgaagtttc actccttcct ttagaaaatt cggtcagaat tcaaataaaa acttaacaat 82620 gcacatcaca atctcagaaa aataagaaca acccaaacta caaactaata cctggaaaaa 82680 aaaaagaata aagaccagta tagaaattaa tgtactgaac tctaaaacac agagttcttt 82740 ctttgaagag aataacaatt ccttagccca aataaccaaa gaaaggcaag accaaattaa 82800 taaaattcaa ggttaagatg aggacaaaat aaaatgtagt actgaaaaca catgaggtct 82860 ttagtaatta atatgaaaag caacatttaa aaagaatgaa gtatctagaa gaaagttata 82920 aattcctcaa caggtatgat ctataaaaat tatattaaaa ggaaattaaa aaaaactaaa 82980 gatacagaaa gcaacaaaac tgaagcagta catcctacca ataaagaaaa gcaaagaata 83040 gattcattgc taaaattacc agttctttat agaagaacaa acggcaaaaa acctcaaagt 83100 gttctaccaa acagggaatg aaaactacta aagccattct acaaaaatat tattttgaga 83160 gttccaaacc aggtaagagc acttagaaaa gaacacacct caaacatact aaaaggctat 83220 aaaataacct gagactattg ttatgttaaa taaaaaaaaa tactgaagtc atttttctct 83280 aatatcagac atgtgacaag ggtgttcagt ttctataata ttattcaatg tagcactctg 83340 aagtcataga gaaaacaaga aaaaccagaa caaaacaaat gggaaagaaa agaacaaatt 83400 atctctgtaa gtacacaaaa gcattcttta cttaaggact ctgataaaca cttgtagcaa 83460 aaagaaagac ataaccaggg cttttctata taaccctaca aagatcccaa gaaacccaga 83520 gagacagagt gacagagaca gacacacaca gagagagaga gagagagaga gagagagaga 83580 gagagagaga gagagagaga gagagagaga aatgaatata gcaaaaactg acaaatgaga 83640 ctgcaacagt taaaaggcaa atcagtagtg aagagacaac caaaataatg gaagaaaatc 83700 tttaatgcag aaaactatac atctaacaga attagtatct agaatgtcta agaacaaaaa 83760 ggcacgtgcc aaataaactg atattccaat cctgcactaa attagccctc ttcctcaaca 83820 ttgtaaaact cttctgtgat aaaaatagaa caatccaacc caagggcata tgtactggag 83880 atctgcttta gccccacatc tgaggtggga cggcatgggg tagggagaga tgccttcttc 83940 tacccccctc tcactaccta cagcaggtag aactggccct ttcccttact gattgaatca 84000 ctcaggagca caggtcctgc aaattgacta taacagctca gaaaagctgg ctatggtgat 84060 gttgcaggta agctggatgc aaggacattg agagcacaag ggctgatcct gcttcattgg 84120 gtaagttaag caggatagtg cttgagagtt gacctcggct gagaaaaata actcaactac 84180 ctcccaagca cagacccagg gcctacccca acatctactc caattatgat ctgctggaac 84240 ttatgaagtt gccagttctg cacatccaaa actgcaggat ctccatgaca cagggtaaca 84300 acaggatatc caggagtcct ggttgaggat ccaatacggc agaacctaga ggcctcaaaa 84360 tagaccaata actcattgca atgaacattt gcaagtagag atgtgtggac aaaagcctag 84420 aaaaacacaa tacaaaaggc cagtaaataa attcttccca acatattata gttaaaaaat 84480 aaataaataa aacacagact aaaggatact aaaggataca agaaaaaagt gacatcactc 84540 ataaagcagg ctcatcaaaa ttaatatcta ttcaacaaaa gtctttaaag catgaagtgt 84600 ctggatcagt gatccttaac cttcctagtg ctgtgaccct ttaatacagt tcctcatgtt 84660 gtgatgactc ccaaccaaaa gattatttca ttggtacttc gtaactattg ctactataat 84720 caatcataat gtaaatatct gatatgcggg atatctgata cgcaacccct gtggcagtta 84780 tgactctcag gctgaaaaca gctagcctgg atcctgaaag atcacaactg gtaacacaaa 84840 gcattacact tgtaaaactt tacacaaaaa ttcaaagaca aatagaaatt ttccatgata 84900 aacagaaaaa acacacatct ttcaagaact ctgattgtaa atggtcttaa ttaatccctt 84960 ctccaaagat acaaaataaa gaaaattaga ggaaaaatct accaggtgga tgttacaatt 85020 ttagacacat aagcaacaca gaggcgcaca atttcatagg aggaatgcta ttagatctaa 85080 aaccacgtgt cagtctcaac agtgactgat agtgggtgac ttcgctaccc aactctctcc 85140 agcagacaga tcatctggac aaaaattaaa acagaaactc tggagttaag tcaaatgaat 85200 gtaatagata tttgtacaac attccaccca tatactaata cattcttctc agtctatgga 85260 attttctaca aaaatcaact acctatcaag acactgaaaa agtcataata tatgaatact 85320 gtaataccat acttctttgt atagaataca atggaataaa attagatatt aacagcaaaa 85380 gatattacag aaaccatggg aactaaataa cacattactg aacaggtgat ctctgtgagc 85440 tcaaagcctt cctggtctac agagctagtt caaggagagt cagggctaca cagagacaat 85500 tatctcctct agaaactaac acccacagtt tattcatctc tgagaaaagc atcataaatg 85560 atgcacaaga aaatatcttc aaacagcaaa tccctgttaa aggaactcaa agacaatata 85620 aacaaatggc tgaatgagaa ctgcagaaac atgtaggtga atcaagtaac acaatcctga 85680 gaaccttagg acacagagga tatctcaaca taataaagga aaaacagaag aaattcctgg 85740 caaacatgtt aaataacaaa tgaaaaaaaa aaaaaaaccc tcagagcatc cttactaaaa 85800 ttaggaacaa aacaagcaca ttctgggcct gtgcttgtta tttcaggtta atataatgct 85860 tgaagtgctg atgagagaaa tactgtaagt gaaggaacta aagaaatcac cagtcaggaa 85920 agaagtcaaa ttatctttat ttacaataaa atggttctat taaaaaaaaa tcctgtaagt 85980 agcaaactgt aagaatctac cagaaaactc ctacagttga taaacactca gcaaagtaac 86040 aatacaaaat gaagacacaa aactcagtag tctttctttg tacaaataat aaacaaaaag 86100 acaaagaaat tagggaaacc atcccagtca caataacctc aaaaattatt tgaataaatc 86160 aaactaagga agtacaagag ttgtataatt aaattttaaa aaattaaaga aaatatgttg 86220 aaaaagcaac cagaaggtga aaaaaaacca cccatgctca gaatgttgta aaaatagtca 86280 ttctacctaa aacaatttac agactcaata taatccccat caaaatcata gcttgatttt 86340 tcataaaaag aaacactaaa atttatttca taatacacat gacagaaaaa caatcctgaa 86400 tagtaaaaga agtgctatca gtatcatcat ctatgatttt aagttatact acaaagcttt 86460 agtaataaaa acagcatggt gctgacataa aaacagacac ttcaagtaat gaaatcgaag 86520 tgaaaacttc ttgatggtaa gatcagattg ctatagacac caaccacatc cttgaatcac 86580 agagcatgga gacattatgc tggtactcac tggaaaactt tatcacaact ggctataatc 86640 cactgtgctg gcaagtgcta tataaactct cttgagaata aaggcctcaa tctcatccag 86700 ttatgaaccc tgaaggctaa aagtggcctg acaagatagg attactaata attgcatagg 86760 tgttttagga gtaactagcc actatatgat tgcattaaag gtctactcta taaagtggag 86820 gccatactat taaaggagcc aagaacttgt gaatagataa ggtaataggc cctagggtag 86880 aacccatacc attactctgc taaatgcaca taatattaaa atgactccta atgattattg 86940 ctatatcccg agaaaagccc attattttag ctttcactag agaagctttg ctccgtaaca 87000 tatggcaagt aacagagatg atcctattcc aaaactggta agcatggcaa gaaaaagaaa 87060 gtgttaagtg ctcaatccca aatcagacat ttatctcacc ccaaagagct ggaaagatgg 87120 tcactcacag gtggtaaata acttcaagga aacagtcttt tccaagagca agagactaga 87180 tgcatatatg aacttatgac aagtcattac gataatacac ccaagctaca gccagccaaa 87240 accccagcat gggggggtgg gggtagagat gtcatcctac cacaagtgtc ttatgaaccc 87300 ctggtaatct gactacacac tacagcaggt cccaattcca agactagcct gacaatgcaa 87360 aactagactc aatggagaat aaaggaaaaa aagtttgaaa aagtataatc ttaaaataat 87420 ggaagggttg agagggctgt aagaggagga gttgaggaag tgattatatt catttagaga 87480 ctagatgaaa ttttcaaatt tttttaaagg aaaaaagaat tttgtaaaaa aaaaaaaaaa 87540 ttaaacttca acctcttgaa ttgttgacca gtgacatccc agtgatcact ctcttccaat 87600 gctggctatt tatttccata gtttttggtt actctccaga acttgacagt aagacactac 87660 tactgaagat ataacacact tcagtaaaga aatggaaaaa ttaagcaaaa actcaccttg 87720 aagcttgatc tctactaact aggatctgta caacttgaca atgctatgca aactatctga 87780 cgagaaaagt aatcaggaga tattcaactt ataaccaacc aatggtcctt agttatatca 87840 cagttcattc ccaaagtttc catatcattt ctgtggtcca atagcaatca ctgactccac 87900 tattccacac taactatata tagtgaaagc atgacccaat aactaatcct tgtatcttcc 87960 aaaataccaa attacagact caataatctc taatttctct tttgttattg cttacttttt 88020 ttagttggta ttcctctagt tatttgactt tgatgaaaaa cttctcagat ttcttctcca 88080 tattagaagg ctaatcttag gttaaagaac cttcaaaggt tcaatctgac caagagtatg 88140 ctcaaaaaac ccagaaaaat ttttgaaaat agaaccacct ataattagag ttcagtttca 88200 cacagaaact taaaagcatc cgatcttata accagaagtc accctgataa aaatgttcag 88260 ctctcataaa aaattctgaa aaaacattca aggatcaaca aggcaaagtg atttgtcaaa 88320 tggcatattc ttaagatgtt atgtattatc cctcataatc acaggctgag aatatgtaat 88380 agttatttag aaataaactg ctaccacaat atatttctga gacactaaat atttttcata 88440 catttaatga tttttcacta acacttagta agcaagcatt aactcattaa ctaactattc 88500 cttatatatt ttgctacgta ttcaaggtag ctttagttgt gaatttgata gtctaatgtg 88560 tagtgtgacc taagggactc tcaattgagg gactacctag attaaactgg cccatgggtg 88620 tgactggggg aaaggggaag gtcttgattg atgtaagagg gaccagtgta ctgtggataa 88680 tagcattccc taggcaggtg gttttggact gtaagtaagt ggtgttagca atgcttaggt 88740 ctgaaaattg agtcagcaac agtataaagt tcctgccctg actactttga acgatggcct 88800 ataacatgta agctgaaata aaccctttac tcccctaagt ttctttttgt tagactgtta 88860 aatataaaca gaacattagg ttcccattct actgagacct taaaagaaat gaagtgatac 88920 taaatctcag aaaggaaaat agtaagaatt gagaagatgg gacacaatca tattttgata 88980 gagatactca gaaaagatac ctatgacagg cattatctaa gaattctgaa acaagtaaaa 89040 aagaaaaaca cgtagattaa ctcaagaggg aacagtcagt aagttccaga actaaaacct 89100 caaaagttgc aggttaagaa cataatgcta gtacaggatg tcacataaat gaaagagcca 89160 gttcagggct gtatcaattt ctaaccatag tttaagaaat aggaaacctt tgaaaagttg 89220 agtatagaaa agatggctta actttttttt aatcagaaaa gcccattgaa ttgttggtag 89280 taaatagagg taggaacaaa agtactgaga aacaatgatg tcccttatca aaagatggca 89340 atggtactac aaatgctttt taaagaagct gaaatgtatt ctgaagataa atgcaacata 89400 acttgcaaac agttccaata tgtgacacaa agagaaacta aggatgcttt ctagaatttg 89460 gtttaaaata aagtcctact aaataagatg caaatgtcta tcagatttca agggattgat 89520 agcatacaaa taacagttct attttggatg aattgatttc tggctttttt ggggggtggt 89580 gtatacatgt gttgtgcaca caaacatgga ggcatgcatg cccatgcatg tgcatttgga 89640 gaccagaaag caaaggcggt cataattttc taatgctcct cacacaattt tttaagacgt 89700 ggtctctccc taaacctgac acttgctgaa ttatctagac tgaatgaaca catttcaacc 89760 accattccat ttctgcccct ccaccaaggc tgggatgaaa ggccttgcct cactttttac 89820 ataggttctg aaattctagt ccacatagtt ggaaagcagg acactgagcc aactctttag 89880 gccctgcttt tagctgcttt ttgtgtttgt ttgtttgttt gtttgtttgt ttaaagccat 89940 gatctcatgt aactttgact tgccttactg tataggcgaa gctgtccctg aataagctcc 90000 caagtaccgg gagtacagaa gtggagcaag caaacatacc cagccaaata tcaaaattct 90060 taatacttct atatgcacaa attcataata tgaaattttc atataatcca cctagatatc 90120 ttctggtttt ctttcttctt ctattaaact catgggctaa aggacatcaa tgtcaatgtg 90180 catgttatat cccagtatta agagtctcca aaattatttg tatttcttaa taagagaact 90240 ttacaatctc tttatttcca accataactc ctttatctta agcataataa acaccatatg 90300 taggattatt aaaatgttat tcgtctgtta aaaacactca ctcatgcaat aataatttta 90360 atatatgaag acacggctgt ttttccaaag tttttatttt cattgacaaa taagaactac 90420 atatattatc atatgcaaaa gtgatacatc aaatgagttt ataaattcta acatagcact 90480 tttgcacata tacttaatag ttgactttta gtgatattca agaaaatata cagaaagaag 90540 tcaccatgct ctacaatttt ggtcctgaac tacattctat tcattttgca ttttttatgt 90600 ctatcattta ttctactcta agtaacaaac aatttttaga atgtttttac agtctatgta 90660 caggaagatg atgcactacc tgtttttgtg ctgatttatt tcattgaaaa tataaaggat 90720 catttccatc catgttgtca ccgacataag atttcagaaa aaaattttaa tggcgaaaaa 90780 ttacatcatc atatatgtca atttttattt gtttagccac tgacaaacac tggtttattt 90840 ctgcattttg tttaattaat gctgcaatca aaattaaact gcaggtatct cttataacac 90900 actatatatt tctataatac aattgctagg tcattgcaat ttttaggaac ctgttatttt 90960 ccataatcga tctaatttac attccaaaca actgtgtaca agatttctgt ttgcttacaa 91020 cctcaccaac atgaacattc atatattcta gcaggtagga agtagtatct cactgttgtt 91080 tcatttctta gatgattaga aaggtaaaga attttttttc tcatgaattt gatgctggtc 91140 atggtggtac aacaccttta atctcacact cagaaagcag aaacaggaga atatctgagt 91200 ttgaagtcag ccttgtctac agagcaagtt ccaggacact caggctacac agagaaaaac 91260 ttgtctcaaa aaacaaaaat aaataaatag gtttttcctc aacacagaaa aagagcaaga 91320 attgaaatat ttgagattct gcaaagaata gaggaaaaga aaaaatatta taatatcaaa 91380 ataattttta aaaactcatt taaccacttt gccatttgta ctcctttttt cccctgtctg 91440 gtctatacca ccttacttgt catcctctgg actgtagtcc agttccacat tctttcacca 91500 gcatagagct taccaatcag attagcccca tggatcctcc tggatcttcc tccccagcac 91560 cggaatttta tgtgtacact accacacact gcatttttat gttgttatga aagttatcaa 91620 atcaggtcct tatgcttctt aggcaagcat tttacctact gagctatctt cctaccggaa 91680 ctacttgttc agaagcacct atttaggtcc cctatccact tcttccatga gctgtctgaa 91740 ttacacattt cataaagtaa ctattcagca tgtgaatgct ttcattcatt ccataggggg 91800 gttatctgtt aactatatct tttcttgtgt agaaagctat tgttttgtat aaccccatta 91860 gtctattttt tgtagttatg tttttaaaac aaaatttaca aacactaatt aaaaagcttt 91920 tcctgtttta atatattagg tgatacttaa aagaggatat taactaagga cacaactttg 91980 tcctatttaa catactggtt tttttattct gcaagagtgg tcagtgctcc taatagctga 92040 gccaccttgc agcctcaaga atgcttgagt cagagagtaa ggcaatatgg cccctgtagt 92100 taggcagact tgggttttga ttttagctga tgttgtttct tttggggatt tcaagacagt 92160 gtttcttgat gtagctttgg gtgtcctaga acttcctcct gactgtctct gcctcccaag 92220 ggattaaaga ttaaaggcat gcaacaccac catactgggc taaaataaat tccacttaat 92280 tataatgaat aataattatg tattgtttaa ttcagttggt tattcctttc tgaagaactt 92340 ttgttactag cctatagtac tagacttttg ttttcatatg agagtaatga cttaacttat 92400 agtattagtt cttcaaggtt tagtgaattt catcagtgat atcattaggt tctgggcttt 92460 atgtgacaaa agacttaatt cctgattttt ccatcttctg atgacacaac attctcaact 92520 ctggccatca ataatagcat gcaaacttaa aatgctctaa tgctaaaagt gttatacatg 92580 aaacactact aatggtttgt cctatctatt ctgctaatat tcaatctaaa atattatcta 92640 ttagagacta ctggtacagt ctaactgcaa gcactatgag gtttctaaac taagcaggcc 92700 attcagtgca tgaaactttc aacatttggt ctgttttttt aaaacccttc atatcttggt 92760 aagttttcag tacactcaat ctcaactcaa ttataactat agtgttccac aaaacatcat 92820 taaacctttt tcaaaagaaa aagaaaaaga aaaagaaaaa ggaaaagaaa aagaaaaaaa 92880 aagtacatgg ggagcaaaga tgtggtggca cacactttaa tctcagcgct taggaggcag 92940 gggcaggcca gtctctgagt ttgaggccaa attggtctac agagccagtt tcaggacagc 93000 cagggttaaa cagagaaacc ctatctcgat ggggaggggg aaaaaaggta catggggaag 93060 gcagttcttt agtttctact atacctgcag ctatctaggt atacaaaata aacgagtttt 93120 cttttaaaca acaacaacaa caacaaaagt tatttggcta ctaaactaca ataaaatata 93180 acctcacatc cattaggatg actattgttc cccaaagaaa ttttaatata cgggtcaagt 93240 tgtaaaaaaa aaatgtataa aacttttatt ctaagaaatg taagtaaaat ggtatagcta 93300 ttgtttaaaa cagcatgata tattctcaaa atattaaaaa tacaattacc atgatattct 93360 ataggaccaa aagaatttga caaaagatta gacccatgct aatcacaaca ttattcacaa 93420 ttgctaaagc acagaattaa cccattaaca aatgagcaga atatagcata tacaagcaag 93480 caagtgttat tcagccaaaa aaaaaaaaaa aaaaggagga agttctagta tatgctacac 93540 ataaacttca agaacactgt gttatataaa ataagccagt catcaaaaca aaacaaaaac 93600 tgtgtgacta cacttacttg agatagttag aagcaccaaa cccacagaca aaaagtagaa 93660 tttaattgcc agccacagtg gaagaaacag gtcactattt aatgcataca aagtttcagt 93720 agggcaaaat gcaaacagtt ctgatgacaa atgctcaaac atattaatat ttacaatacc 93780 actggctcat atactttaga acaataaaga gtaaatttta tacattttat aagtgtttta 93840 aagttatcag agaagttaca tggtctcaaa aatttaaagg ataattcata gttgtttctt 93900 aagacttcac aatgtactta agcatttaaa gggatgtaat ctgcttctag taaggaaaac 93960 ctggactttt tcaaccacac cttaaacata gctatacaca tctatcttta cttcctcctc 94020 atttcttaag acaggaatgc atatgtgtgt gcattaacat agatggtata ggtagattta 94080 tacatgtaga gaggtgtgtt tagaagtcag aggcttgttt tcactatact caaagcttgt 94140 caattatgct aacctagcag ccagcttgcc tcttactcca gtcttcttaa tacttacata 94200 gcaagtgcta tattcaccaa gtctttgcca cagtcccctg cttaattcct tctagttatt 94260 cctattttca tttttcattc ctcattgtca aattttgaaa aggttctcaa tttcctactt 94320 ttccctacac tcaagtgtct tgcttcagaa ccttggcaat gacttggcct agaacactgt 94380 tcaaatatcc aactgcttaa tccccagtaa catttcagga ttcaacctag ttttactcag 94440 ctataccaat gttcctacta tgcactagat ttcttttgca taatttggta ctcctctgta 94500 ttcccactgt ataccaagta taattctatc tcaataatta aaaaatctga ttctgctctt 94560 tctgaagcat tgagatataa gtctcaagca tctttatacc caaaacatag cacctgatga 94620 ttaatattta gaacaggggt catatttaaa caatcttgct ttcaggaatt ataaattaat 94680 agcaggcaca tagatgtttg aatcttcctc taattcccct atttatcaac aactgccaag 94740 ggcacaaaaa acattgaaaa ttcagaatca tgtatgtaat tatctactta ccattagaca 94800 tctaattttt tgcagaggtt tggaagtatt tggttaggag atataagtag acatgttcca 94860 atctctagat acaatttaaa gttgttcctt ctttttcttt ttttaattca attttacctt 94920 tttttatttt aagcctgaaa ggtattttca aataaaatag tgtagggcaa cttgagacac 94980 aaaataacct gaacgaagtt atacttacat tcggctagct tcaatgtcct cagactggga 95040 ttctcctggt gatctgtaaa atgtaattaa agacaaatat tagtgatttc caaaaaaaag 95100 gtatagaaat ataagtaagg aagataaact ggaaaacaag acttaaattc caatgaaagg 95160 gtgctttaaa agatttaaaa ctaagaaaaa aaaagtagaa agatcagatt atcacaacac 95220 atttaagaac aaattttaga aacctcaatg tttaaaaaga aaattaaaat ctttatattt 95280 agatatcaaa ttagtataag ccataattat ttacaatgtc aaacacatat taaaaaacaa 95340 gactgttact ttctattaag ttgggttgtg gtattcatag tcttgaaatt aaatgaagtg 95400 tttgcaaact gtaacctgag caaacactaa ggtgtaggat aatcaccttt attttgaagt 95460 gatattatac tgagagattt gtattcattt atacactgtc tatgtattca gaaaaagcaa 95520 ggataagtac ttgcagaaaa aactatttcc ttcaaaacct aaaacattat aaaaaaaaaa 95580 aatcccttga aaaatgtctg ccaatttctg cagtagacaa tttaaactca aatataacag 95640 tgttcataga tctttaagat atttaaatgc tatgcaccat tctaatcata attcctgtgg 95700 ttctataagg aaattagatt tccctaaaaa gcactatctg ccgtcaccgt gtatatggag 95760 cattatgttt gctagataat tgtaggctag ttttagtttt aatatctgct ggttattttc 95820 tttatttttt aatatattag ctaatataga aatacatata aagcaccaaa gagtatccca 95880 tttttattgg gtggaacata agccaatttc cctattctga acatctggtt aaagaacaaa 95940 ttccagtgat gcacacagca atactttgct atacttcctg tcatcagaat gctaaaccag 96000 gatttagcat gaggacaggc tgttctacat agtgagacac tgcctcccaa aaagaaaaaa 96060 atctgttacc ctacatatct ttactgtgag acaatcaatg ttctaaggta aatttatttt 96120 aatacctatt tctaatgctt taaattccca aaataggtta agaaagaaaa gaataattta 96180 aattttcaaa tttgtataca aagacaatct gtgaatttac tactgacttt agtctttcaa 96240 gttaaagact tgatttgtaa atttatcact gacttcagat attcaactta aacaaaaagt 96300 ttataaaagg ctggttgtgg cttatggtta tggaagattt tttaaagcaa tgattcttaa 96360 gttaggggat aaagaagagg ctcactagtt aagagcactt actgctccca gagaaatcaa 96420 ggtttgcctc ttagcaccca cacagctgct cacaaccatc acaaactcca gttccagcac 96480 tgatgccctc ttctggccta tgtgagtatc aggtgcacat gtgcatctgg tacacacata 96540 catacctgca agtaaaactc acacacagaa aatttaaaaa tcttagccag gcaatggtgg 96600 cgcacgcctt taatcctaga agttggaggg cagaggcatt ggatttctga gtttgaagcc 96660 agtctggtct acagagtgag ttccaggact acacagagag aaatccctgt cttaaaaaaa 96720 caaaaaacaa caacaaaaaa tcttaaaaat taatgtattc acttctttag tgtcaaagaa 96780 atttcacttc tttgcttgac tttcaaaata atactcattg taattcattt agattccaag 96840 tcagtaacac acacacaaag aaaaaggaaa aaagatacga ttaaaaacag accccaaaag 96900 ctcagacagt ttagattttc ttagtagttt atttatattt ttctgtttat cacaaaatta 96960 cataagaatt gaaaaatgta gattaggagt gatatcaaat aaaaaattct ccaccctctt 97020 cccccagaaa acaagcaaat atctcagaaa taatgatctc tacagcctta agaaactacc 97080 aagattgttt ccaaacttat atctcatata aaatggctag aagagttaaa acatgatggt 97140 aacccatgca ctagctaact cattttggaa tgtgtctttc caacatctca tatattatta 97200 agactgtgag ataaagctga cttgcaaaac aacaacaaaa acctgttagc aattaggaag 97260 ccaaattaga agtctctaaa caggtaggaa gcaaagtgtt ctaaatgtac aggaaaagaa 97320 aaatttagag aaggttaaga atgatgagag aaaaaatatt atataagaaa atataagata 97380 agagaaaaaa agaactatat ctcaagagaa tattatagaa ctgctgcagt ttcaagaccc 97440 taaaatgaac tatagaacaa acatattgtc aaatggccaa ctacagctat tttcgcaatt 97500 tctgattgct acagagtatg tgaatgccag taacataatg ccaaccaagt attgtaaata 97560 tactagactt ctatttaata ttcacaaata ttagagtaag ttattaagca ccatttagcc 97620 aaactaaaat ttaagaaacc ccagaaagat cagagtaaaa ttaatccaaa caaattattc 97680 ttcttaaatt atactcttct tgatctctta gacatagtat agcagaggct gctcccattc 97740 aaacagtttt actttagtca agagaaaaat atataaatac aacaaaagca tgtttctgat 97800 cattgtgtac atctgaatgt ctatgcagac aattttaata atattctaat taagttgcca 97860 aaatatatcc taaaactaga gttaactttc aaagtaactc tatttttata actattagta 97920 ggtgttacaa accacaaagt atatgtaaca cctactaata gttataaaac tgttctctgc 97980 tcttaaaatg cttgctgctt tttactgaca atacatttga aataagaatt caggacatgc 98040 tcctaatttt accaaattca aaatatagaa ccaactaaaa gttaataaaa aatccactac 98100 caacccaaga ctgacccaag ttatcctaaa gtttaccaga atattaataa aggaatgaat 98160 gaaatttgaa acctgaaaaa tacctagtaa caatggtgag gaaaaagtct tttaaaagta 98220 tcaattttag gtattaactt taaagacaga aaatgtaatc acaaaacaaa taatctgaac 98280 actggaacat gacctagtaa atccatcctt ttaaggaggt aaaggtgcac ttttaactcc 98340 actgtaactc tctaggagaa aaagtacact cattttacta aaggtgcaac atttctggag 98400 aagcactgaa actcctgcca cataaaatat taaaaataat acttaagata ttttccacat 98460 atctcttaaa atgtccacac tgtaatcttc aaaatactta agacatattt tcttattaat 98520 ctatgcagaa aaacaggtct ttgatgatta cttatcttca tgaactgaag ggtaagtaag 98580 aaatgcacta taataaatat ctgagaaagg aggttaaatg aagaaatggc tccgttctta 98640 ggtcttttat tcttagcaat attcctgcta cctatgcatt tttgtcattt ttatagcaca 98700 taattcatct tacaatgaca gcctttctaa gactgtaaaa taacattcaa aattaccttt 98760 tacaagctgt ggccattcgg tgacatcagg gtgataacag ctttgagtca ctgattaaaa 98820 acaggttgtc acaccagtct agctgctaac ttgatctgaa cgtaggctta ataattctaa 98880 taaattaaac aaacctttag ttagaacact agcataaacc caattcattg ttcaagtcat 98940 tatcttcaaa gctttaaatc agtagtcaat ataaaattag aagaataatt atcacaggaa 99000 aacctttatg aactattctt cagtatattg ttttcttaaa tggtctcttc atttgagaaa 99060 atgaggtata ttctcaatcc aaaactactc caaaatccag aatgttttaa atcatcatgg 99120 cagcaaataa aaaagggctg gatttaggaa tatttccgat tttgaatttt cagactaggt 99180 atgttcaaac agtaaagtct ataggaacat gccaaaatct gaaaaattct taaatttgaa 99240 acatagtctg gtcccaggca tttctgataa agataataat ccctactttt caatgtagta 99300 ctatatggct cacaaaatac aacaatcaac tgtaccctta cattccactg actttagctc 99360 tacaagatca aaatagaaga ataacaataa gcagcctcag agtgattaac tgacttgccg 99420 aagattttgt aaataatgtt gaaattaaga ccaaaaaacc aatatcagct aaatttccac 99480 taagtattag aattttgcta tggtttagtt ttgctttaca gtgttttgta atttaaatac 99540 atacaaaaag caaaaattta gactatgtat tgtggcagta attagaatga aactgattta 99600 gtatcaagag tctttaactg atgggagaaa tcagctacca aacaggcaaa atcttgatta 99660 aagttttaca cacacacaca cacacacaca cacacacaca cacacgcacc cacacatgaa 99720 agagagagag agagagagag acagagacag agagacagaa attatttaag tagtataatc 99780 tatcattaac ttttagacct ttggatctat aagaaagcat tcgttttcaa tcccactaag 99840 actcaattct aggaagtaat ataaagcaaa atatgaatga atatcctatt attcacatat 99900 ctgaactatc atatgtgatt ttaaacaaat ctgattcgtt tcacagccct ccttatcata 99960 ctatactcct gacaaaatgc caatactgtt atggttttat ccagttttcc cccaaaatcc 100020 tctttcactg atctataaac atagaacaaa tttgaatgag cttaaaacaa aacaaaacaa 100080 aacaagaaag aaagaaagaa agaaagaaag aaagaaagaa agaaagaaga aaagggagtg 100140 taagattagg aagaggaagc cccttcacaa ttaacaccct caaattgaca gcacagacaa 100200 gccagatggc tgaaagcacg gaatcagaac ccaacttaaa acaggaagta gtgagaatcc 100260 caaaggaatt attaaagcat caatatttga acccatatta ttgttagagt tggctcaagt 100320 ttatattata tatatatata tatatatata tatatatata tatatatata tatatataaa 100380 caaaatcagg gggtcccaat aaataggatt tataacccct gttaagaaat aacccaattt 100440 cccaaatttc cctatcataa ctatttatct tctactaaga acagaggcat cactgaacta 100500 gcaagggaga gaaataacat ccttgaaata aatgtggtcc atggcatagt tcccttagtt 100560 tctcatcaaa cagcttatgt ggaattatgt gaatactgaa atgaatctaa cttctaactt 100620 acaaacacaa agataacaca gcttaaataa aatcaactaa ttcattaaag aactatatat 100680 actcttagga ttactaaatc aagtactctc cactagtctc ctctttatta ggttcaatgt 100740 tcagttgaac agtttccaaa gacattctaa gattccactc tccatgatca cttactatag 100800 ggaaatcttg gacaagttac ataacctctc taaacctcaa ttatcttaaa gcagaattaa 100860 aaccctagtc tgggttatca taagagtgcc ttatataaaa tatgtttgca aataaatgaa 100920 agagattttt catacccaca gcctaacagc caagtctatt tccttgacct tcttgttcat 100980 attactttgt ctcataatac agtaaactca caaattcttc caacacccca cttatatccc 101040 tcacagtcta cctggttgta tactcagcac ctagtaagag tctttaaaat tgacaggcgc 101100 ccaaatttat tgaacgcatt tgtcattata ctagccgtaa tattaaaata attcatgcaa 101160 tatgaatttc aaaaaataaa acagaaacat accatatttc gccaaacttc tgaggagctg 101220 gtgaactcta aaatcaggct cttagagaga ttttttaacc taaaatataa aacacctcac 101280 tcaattcttt taacataaac tggatagtct ttcagaaaaa aaattactca aattcattat 101340 aaaataaaag ccaatttctc ttcaataata cttataaaga tccaaaaata tattgaaaga 101400 caaattaccc cactcctatt gccaagaaaa gtagcagggt agctctgtag gctgtgagct 101460 gaatattttc cgactaggaa agccatgttt cccatcttca tgtacaaaaa gtaatgctcc 101520 acaatccctt tcctcaaacc ccttcagata tctacagtaa gtccacttcc aggtaatctc 101580 tatatgaaaa acttctgcta tataaaacct agagtagcaa ccatggctaa atcctctgac 101640 ctgtcagtct ctcaagagtg ctaagttgtt gaattagaga aaatgtataa aaagaatata 101700 gatgctttcc tgacacataa cagggctctg ttactcaact aagtcactcc atgtctatca 101760 caattcttta caaataaaca ataacaatgt acttattaca gagcttaaaa caagctctcc 101820 tatgatttta aatttgtgtt catagttcat ttataacttg tcttgaatat ttttcagcct 101880 ttaatatctt ttaatcttat tttgtcataa ggagaaaacc taatcctatg gattaagcaa 101940 ctacaaaata aataaatctg catattattt ataggtaaat aggttggcag gtaggtgagt 102000 gagaaggaaa gaaggaaagg caaatggatg ggctgataaa tgatggatgg gtgggtggat 102060 ggacagacag attaataaat tgatagatgg actgatataa cactatggtc tccccaaaga 102120 taaactttat cacatactag taaatcctgt ggcataacag taggattctc gttccaatga 102180 ctcaaatcag aaaagttcaa atcatcctgc caaatataat atattgctca ctcactgcta 102240 ccaattccac ctcagggatc tccccacaat ccaacactat ccctaataat tctccagtgg 102300 cctttacttg ctttcggtat agcttaattg ctccatcaca atatgtaaaa ctatgtttcc 102360 aaaccctgct agtataccct tccttccaga ctagacaaaa cattgagagt atgtccttaa 102420 tttttatact aaatgtttta aaaggtttat agaataaaac agcacagaaa aaaaaaaaaa 102480 aagaaacttg ggtagctatg taaatgcaag gctaagaaac ttcaatctgt ttcaaaagac 102540 tatccatgtc catttcctta taaaccagtc taactcaaag tcacgccgga aaaattagct 102600 ttaaaattct tttttgtaat atttcatctt taaagaaaga atccattgct tcttttcccc 102660 acatggttac taagattgtt gtgatacaga gtcttgtcat tttacctcat ttctctctta 102720 catatttgac agaactatcc tcctagaaat tagaatttgg tcatatccct ctcatattaa 102780 aaaaaaatcc ctatgccttc tcaattctgt taacataaat ttcaaacttt tttttacata 102840 ttaactgatg tccttgtcat atggtcacat ccagtaatcc aaacattacc catatatgat 102900 gacatcctga aatatcaatc tcccttggtt attgtactct atcatatatc agaaatctct 102960 atttctggtc ctaataattt tgcttctcag gatattccac aagaaatgtt ttcctgtgct 103020 ctgcaatttc catcctctct ttatctataa aagcctattt aaaaaacaaa caaaactatt 103080 cttcttaaaa ctttagagca ccccaaatga acaatgacag ttaaggactg agaatgacaa 103140 taacactaac aatgaaaaaa atcagaacct tcacatatta ctaataaaag tatttcaaag 103200 gaatataaat atatagccac tttgagaaaa gttttaaaat gcctctagtt ttaaatagtt 103260 gccatatttc ccagacaact cacacctaga tatataatca agagaatgct atatatttac 103320 aacaaaagtt aaatccatat atatgtatgt attatatatt atatatctat tatataatat 103380 ataattattt atgtgtgtgt gtatacacac acacacacaa aataccataa caacccaaaa 103440 tgaaagcata cagaagccca tatactgatg actggacaga taatcagcta tttaaaaaac 103500 aaacaaacaa acaaacaaac aaaaaaccaa aaaaaaaaaa gaaacaaaaa aaaaaacctt 103560 gtagagtttc ttttctttta aatttttttc tgtaaattat aaaacacaca gaaaattgct 103620 tagcatacag caggccctgg atttcaaact ccagcactta aaaaaaatta attaaaatca 103680 ttaaattgaa gcatgtagaa aaaaatcata aaactcttat cattttacca accactcaga 103740 attaaagcaa acacaaaaga tgccatttga tatcattatt taaaatctaa ctattccaag 103800 tactggttag agatgctaga aacaaaaatg ttcattcact ggtgatacag tatatgttgg 103860 caaatcaaat ttacataaaa tttgccgtat ctaatcaagt taaggatata tcctattttc 103920 taacaacttc atccctttaa ttttccctaa agaaaacctt ttacaaagga agtataaaaa 103980 tgatctgcgc aatataggaa gcaattcaaa atattcataa gcagtgggat acaatactat 104040 ttagttatcc atatactata ataccataaa agatatgtgt caacatacac atctcaaaaa 104100 cagataaaac acataaaata aaacacataa aataaagaca cataaactga tggcaagtat 104160 gtatgaaaca catctataaa ttcttaagca tgatatctca cttattggca aaggtcatat 104220 ttaagtacaa aacagaagat attcaagaac ttcaagaaat ctcttacatg gataagaaga 104280 gagggtatta ggacttggag gaagagatta agtttccaaa acaaaaatca aaactggcat 104340 ttatattcca ggatggtagg taagtagatt attgatatac tattaagtgc tttaaatatt 104400 ttataacatg ttttaataag aaacaatctg aatatacaat ttctaagcta aaaacaaaac 104460 cctaagacta tggagacttc catgacacaa tcttcccaat ttattaaaag tatgctaata 104520 agataaaaat gtatggctct tgagattatc tccatgagta ggataaagcc atataagcct 104580 gacactttaa aaaaaaaaaa aaaacactct gggattaaag ttaaaaattg agagacctta 104640 atctacctaa ctatcctctg acctccaccc gcatcacagc atggcactct tatgtccaaa 104700 tacacattat acaacacata atgataataa tagtaataat aattcaaaag attaagacaa 104760 aatataaagg actaaaggac tagaagaaat gttccctggg tttaatgcca agaacccccc 104820 ccaaaaaaaa ctattattat aacatgataa ttttaagcgc agaataggtg tctaaataat 104880 taagctatta tctcttgacc actaaaaaga cgaattagta tcaattttta aaagaccttc 104940 agaaggtctt tgttaattgt ccaggccact atagtactgc ttaattctgt ttacctttaa 105000 attctcaagc ctagagaatt atgtattacc atacatacat atttcaagag cctacagcag 105060 atatcctaac ccagacctga acaatctaga aagtagttca ttcaatccaa catttacaaa 105120 tacctgcatc tgcagaaggg aaaggaaaag gacaaaaggg agagaacagt gagagaggaa 105180 agaactggga gacatgaggt tagaaagaga gaaaaaagag aagaggaaag atggaaaaag 105240 ggagaagaca aaggatacag aatacaaaat gtgtacacaa acatttactg ttctcccaga 105300 ctcttcagta taggaataga catctaattt caactggtta agttatgtgc atatatctgt 105360 ttttacgttc acctcttccc tgtgtttcat ttaactcaaa aaaaaaaaaa aaatggagta 105420 agagaaaatt tcagaatcag tagaaagatg atccatacaa agttaaatca gaccaaaaca 105480 atctttcatt tttaaagtga catgaaacat aatgtaccag ccagtaatta tacatgatgt 105540 taagtacaga taaaagacta aaattagctc agttctccta ctatgcttta agagctctta 105600 ctttaaaatt atatagccca atctgtagag gaaagtatat tcctccttta agttcctaaa 105660 cttgtacata acttcttatt cccatctcca gtctagaatc ctgtacaatg ttatagaatc 105720 agtgagaaac agtaacagag aggatggaga atgggacaga atttccaagc ggagaaattt 105780 catttctttg aaactaagga tttggatttt cttaatgtat tttctatcag taacacatga 105840 tacagagtca ggtcacttca aaagtgagga caaaaacata ttctctaatg agtctttatc 105900 tgaaataaga tttatctatt attatacata ctatacaaca ggtactcaaa aaacaacatt 105960 ttaagttacc aaacaaaaac acatttagca aaggcaaata ttatctttat ttttagcata 106020 ttgtacgctt agcaaatata tctacacaaa ggggcatagt aaatagaaat cttaagggag 106080 aaatactaat aaattgaggc tactctactt ccccttagga tgcactaggc attatttttc 106140 ttaaaaaaga aaaagaaaaa gaaaaagaaa aagaaaagaa aaaaaaagaa agagggacta 106200 tgcatttcat cttttccttt ccaaaaaaat agcagtatga ttcacatctg atactaggta 106260 aagtgctgaa acctataatg agaagagtgg tatcaactaa tgaaaacaag gaatgagttt 106320 cagaaaagac aagaattcaa ggaaataaca aaatataaag tttgttcaaa ctaaatggta 106380 cattacatgg ttggtttctt ttaatttctt ctatattgtt catatcttct atatttaact 106440 agaggtatca gcatttattt tatatcacag attataaaac taaattaatt atggccatgg 106500 ttccacaatg gtatctctaa gactactttt tcatatcaga aagtccatta gaagttttaa 106560 gtgaatagcc atctctttta ttcaaaaaag caaaaaaaca aacaaataaa aaaaacatag 106620 gtttttgttt taaaaaaaga aaaattttat cacattaaaa cactgttctg tcgggcagtg 106680 gtggcccacg cctttaatcc ctgcacttgg gaagcagagg caggcggatt tctgagtttg 106740 aggtctccct ggtctacaga gtgagttcca ggacagccag ggctatacag agaaaccctg 106800 tctcaaaaac aacaacaaca acaaaaacaa aaacaaaaaa aacaaaaaac caccgttcag 106860 aaaagtacaa cactgacagt atcttcattc atgtcatagc tatgtaattt gtgtgccaaa 106920 ctgcttgctt taaatgtcca gaagaacatt ctgaattgaa gatatatgca ttggacacca 106980 cacacacaca aaaaaaattg gttcacaccc atagtcccca gcactggagc agtgtaatca 107040 gaaggataag taggtgaggt tatcttcaac tactaagaaa ttgagaccag tgtggactac 107100 aagatattct gtcttttaaa aaaacatata aaacaaacaa gaactaaaaa gtgtctcagc 107160 acttgggccg aagaccaaga attcaagggc agtctgcact acatgtccag atacagtcta 107220 tcctaggtta cataccatga tttttatcaa ctactactac tccgccgcca cctccgccgc 107280 caccaccacc actgccgcca cagctaccac catccatcca cgcacacacc cacacacata 107340 ccccatcacc attcaaacta gatttctaag gctccataac atattttttt caaagtattt 107400 ttttcaacct agtgatgtag ctcactgcta ggtagcaagg ccctgtattc tatccccagc 107460 tatgtaaaac taaaattgaa ggattttttt taatatctga tttctgtcaa attaatgaga 107520 gttgtgctat actgcttaaa tgatgttgac aggtaagaaa gaccaaattc tgaaatgtac 107580 tgagctgctg ctaagagtaa caacagatta cacacaaggt tatgtgtaag gaaaatttta 107640 tcctgctcat ataaaaagtt cagtacctat atactactac tactactact ctggtttcac 107700 tcaaataagg atgccagctt cagcaagatt tacataggat tctccttcat aagcctaatg 107760 caatttcttc gtgaggcttc tcctcagatt tgctacaact gaactgcaag aataagctta 107820 actatggtac tatggcccct aaaggctacc ctttcccatc attcttataa ctgattcact 107880 tgcaattcat ttaattaaaa atcaggtcaa gaagagcaaa tgacaaggaa ttcagctttg 107940 caaataactt atcactaaca atttcatgtt aaatgtacat tacttatttc taggttttac 108000 ctgaagccac agaagtaata agtgcttcag aacttcagtg gtttaggaaa caaaacaacc 108060 taagcttatt gaaatagtta tcaaatctga aactaattca tatattgtaa ttgcggctgt 108120 aaaggagata tacccctgca atcccagctc tcaaaagagg tacataccag aaagaccagg 108180 aggcttagcc atgttaacag aaaacaatat aaccgtattc catcatcctt tctcctacaa 108240 atttcctggg caagttactt tctttataca gtatctatca atgttcaaga agtatcacat 108300 atgagcagca taatcctctg taacaagaag gcagtaccac tttaatatga ttaacaaggc 108360 cttagaaaga taaatggcct gctcctattt agctcactct ggctcaagac agatgtcagg 108420 aaagcagcaa cttctgacaa catgaatatt gcattcttta ttccatttca ataatcctaa 108480 gttgttttgt ttcctaaacc actgaaattc tgagccattt acttattctg tggcttcagg 108540 taaaacctaa aagtaataag taatgtatat tgaaacctct ttcaaaaatc agtataaaaa 108600 atttttttca tgtatagata ggcccaatac ttataatctt tccaaattac tattcattag 108660 tttagttgtt atagacaact gaaatcaaga aagtataggt aatattttga aattaaatga 108720 aaacaaagga aatctgatgt gtacattaat aagtcacttt attaagaagg aataagtgtc 108780 atgtatttca agcctttcat ggttggaaaa agaaattgag aaaaataata atatttctac 108840 ttaatacaat ttatttcaca tcttttattt aaaagaatta aatcctgtgc tatcttataa 108900 ggattatatt ttactaatag tataaaaata tataactcca taaaagtgaa ttgctaattg 108960 caaaataagt gtagctattc ttccaaacaa acatctctga ctcttattat tgaatcagaa 109020 tggtaatcat tgtccaaata aatgagtcct aacaggctga gtagcatact agactaaatc 109080 tatttcattt tatatatacc acatgtgcat gtgtactgta aaaggatatt gatgggctgc 109140 aagtaagaca tgaacacata taccaaggat acaaaaaagg atacaaacag tatcctttac 109200 aattgtagct aaggggttaa gggatattaa gtctacagaa ctgccctaaa actggagggg 109260 cacagacaat taaattccat aacttaacag aattatcaca ttaaaaaata aaatggtgtt 109320 atgtgcaata aataaccaac ctatcagttt ccaaatgata gatattttct ttttttttaa 109380 cccttataac ccatgtcagc tcacacaatt caaaggagcc tcagaaacac tacctgatac 109440 tgataactat ttcagacata ttcttctatg tgatctgaat ctttgcaccc ccccaaaaaa 109500 aaacttcact aaaagcctaa aatcggaggt gatgaaatta caagtgtaat ttttaggagg 109560 acctacattg atgaatgaga gcaatgtcct aattttaaaa gaccatttag tcttagctga 109620 agcaggtgga tctttgagtt agaggccagc ttcgactatt tacctagctt cagaggctag 109680 tgagagacac tgacacaaga aagggaagcg gggaggggaa aaagacaaaa gaaaaaagaa 109740 aggaagggga gggaaatata gggaaggctg gagagatgat tcaaaagtta aattaaaagc 109800 acttgttgct cttccagagg acctgggttc aatttctaga gcccacatgg caattaacaa 109860 ctgtctatat cccagtcaca gcagttccaa cactctcttc tcacccctac agacaccaca 109920 ccaatgtgga ctctcatata ataaaatcaa aaaaagaaca aacaaaaaca aacaaacaaa 109980 aaccctaata aacagagaca gagatacaga gacatagtga tactggcctg caatcacagc 110040 tcctatggaa ggcggcagga ctcccatttc aaggtctgag ctggagtgtg tacagaggac 110100 taggaagtgg tagagcagtt cctagaactt gagaggccct aggttcagtc cttagtcctc 110160 ctaacactac tcaaatttac aatgaaaatt agttctgatc ttaagatttc tcagtgtcct 110220 tgactgtgag atacattttt tggagttggg gggaaggggg gtgttgacca gtctttggta 110280 ttttataaat aggccaaaca gacttaagga ttctggaaac atagtctgag gccagcctgg 110340 tcaatacagc tagctccagg acagccatgg ctacacaaag aaaccctgcc tcccaaaaat 110400 attaattaat taattaatta aagaaaaaag ttttcaatta cacattctat gacatctctg 110460 attgataact tttttgagac aaggtctcgc ctcttagtct aggcttgcca caatccttcc 110520 ttagcctctc aattgttggt ttacagatgt gagacatcat gcctaacata acattgtctt 110580 tatttttatc agtaagaaaa agtaactgtc aaaaccaaaa ctctattatc ctaagccttt 110640 ctgaagagaa catcaaaaga cttagaggac tatttttata tttttatatt gtttttccgt 110700 atttgaaagt acttaaaaga ccacctctta aaactcatct ccagttgcaa aaatcagaac 110760 actgatgttt ttaatagctg catataaata taatataaat ccattaacag taatattatc 110820 aataataaca aacaaaccta attagaataa atgataatat accagtaacc attcatttaa 110880 ggtgttggtt tttttaaagg acatttgaaa agatcatctt aagctcttga acagaaaaaa 110940 aaatagctat ggccaattaa aaagaaaatg ttcataaaaa ttgagagaaa caattattac 111000 tgcaattatt tgagggaaga cacaaatgtt taagaaatac aactgaataa aatttacatg 111060 tcagagacat tatagatacc taatgaatgc aatgttaaaa aaaaaaaaaa aaaaacgaat 111120 caaatagaat gagttttgtc tcaggtagaa atcacatttt tctaatttaa aaccataaaa 111180 agggtaaata gccggtcctg gtggtataca tttttaatcg cagaaccctg gagacaaagc 111240 caagaggaga gttagacgtc atccagcgat ataccataag accctttctc aaaaaaaaaa 111300 aaaaaaaagg gtgatggtgg ctatttcagg gataaaaaag ccacctacaa aacctgcata 111360 caaaaggaat tttctaaact caaagttaag ctcctcagtt atatgaagag caacatccaa 111420 agaagtatgt gtataccact tcacaacaca ccatgcaagg taaatattga cacaaattat 111480 ttcacaacct acattctgat tttgaaaaca aaactacaag tcatctcatc tttattatgt 111540 gctgtatctt tcttaaacga tagactgcga attgttgaag ttctcatttt tattacagat 111600 tctgatacat ggcttttttg taaagctaag tatttatgga tttacagtca tccttactta 111660 ggcttatcag caatacagat gcagtatcca cttccttaaa agtgcagtaa gcagtctatt 111720 taagaggaga atttaatact aaagcaattt ctgtcataca taacaagaca aaattttcct 111780 tttatctctc ctcaattcta aatttacata atttaccaaa aagatatctt aagagtatta 111840 actaatctga ggtgtgtcaa aaacattcgt cgtgtctctt gtccaatagg gctttgatat 111900 ttagcttttt aacagctgta tttcttaaag ttcaggccat ctttatttca aacgcacttc 111960 cctatccaaa acattttaac ataatctgct gcttctccca aaaccatggg ttatacgaat 112020 atccttcacg aagtaagata atggtggata acacatccca tatactattt agttaacatt 112080 tccaacagta cactagctat ttaacgcaat cccaaagaga ttttatactg ttctatttta 112140 gcatgctcaa aagacataaa aaaaattgac gtaaaattgt ctttagagga ttcttctaaa 112200 gctgataaag tcttattaaa attatacttt ctatttttaa ggctaacgca attatagcac 112260 attcaactct gattcttcca acaaaaagcc tccgcatcaa aatggggaaa acgtcctttt 112320 cattttctca actgaaaagg gggaggggag aagaggagga ggccaactgc ttacaggttt 112380 gcattgaaaa ttaacacagc agtttctgag gaatcagtaa ctcacgttca actactgaat 112440 cctaccagaa gcagcacacg aataaaacca gagcgcaatc cttgggcttg aggtgccgct 112500 tcatccgtct tccttccaat ccacccccaa taccccaacc cactaagcac acatctaaat 112560 atgtcttccc caccagagcg cccctttgga ggaaaaggcc tgcctttcgc agcctgaagc 112620 cacggctggc tctccgatct ctgcttagat gaggcccccg atctcgacgc cctgcacgtc 112680 cgccccaccc cgggcccact cgggtacccg tgggtgacaa aaccctccct cctgcgtcca 112740 gccagcactg acagttaagg ctgcagcagc cgcagccacc agggcctagt cctggcaccg 112800 gcccctccag accacgcgcc ccaagcactc gctcacggag gcgggtgagg gcccggcgcc 112860 taccctgtca gcgcgggccg gagggtgacg aggggaccgg cggtacagac cagagggagc 112920 gcgccgggca ggccgcagcc gcagcagcac tgacctgtcc tcgcccccgc gcgtgggctg 112980 cggccctcgc agctgcggcc gcctcactgg tccttgtcgc cctcgtccac cgccgccgcc 113040 cgccaccgcc tcgttccctt tcgctggcgc caccgccggg tctcatgcgg gacccgcgct 113100 tctcctcagg aaaccgaggc cgagaggcca ggcgcctggg caaccttgaa gtcggcgctg 113160 aagcgctgct gtcgcgatct gtccacagtg gggggcgagg gcggcgagca actccgaaga 113220 gaagcagaag gaggcgccac cgtcagcgac aggtcgacgg aagagaagcg taacgaggcg 113280 gtgaacagct gcgtggcccg gtgcgcgagc gagagagcga gcgcaggagg ggcgacgagg 113340 tgctggcaaa gacgaaaggc cctgtcgtct cctggagtca cccaaagagg agcgccacca 113400 tcttgggaga aatacggatc tcgcgaacgc agcactggac gagaggacta ggtgggcgga 113460 ccgagtatcc cgacag 113476 <210> 4 <211> 19 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 4 aacttcatca atatttccc 19 <210> 5 <211> 18 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 5 acttcatcaa tatttccc 18 <210> 6 <211> 20 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 6 caacttcatc aatatttccc 20 <210> 7 <211> 19 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 7 caacttcatc aatatttcc 19 <210> 8 <211> 20 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 8 ccaacttcat caatatttcc 20 <210> 9 <211> 20 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 9 cccaacttca tcaatatttc 20 <210> 10 <211> 20 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 10 acccaacttc atcaatattt 20 <210> 11 <211> 19 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 11 cccaacttca tcaatattt 19 <210> 12 <211> 19 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 12 acccaacttc atcaatatt 19 <210> 13 <211> 18 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 13 cccaacttca tcaatatt 18 <210> 14 <211> 19 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 14 tacccaactt catcaatat 19 <210> 15 <211> 18 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 15 tacccaactt catcaata 18 <210> 16 <211> 19 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 16 ttacccaact tcatcaata 19 <210> 17 <211> 19 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 17 tttacccaac ttcatcaat 19 <210> 18 <211> 19 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 18 atactttacc caacttcat 19 <210> 19 <211> 18 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 19 tactttaccc aacttcat 18 <210> 20 <211> 20 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 20 ttatacttta cccaacttca 20 <210> 21 <211> 16 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 21 tcactgttct gacttt 16 <210> 22 <211> 20 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 22 ttcaatctct atctcatcat 20 <210> 23 <211> 20 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 23 cttcaatctc tatctcatca 20 <210> 24 <211> 19 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 24 ttcaatctct atctcatca 19 <210> 25 <211> 19 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 25 cttcaatctc tatctcatc 19 <210> 26 <211> 19 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 26 acttcaatct ctatctcat 19 <210> 27 <211> 20 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 27 cacttcaatc tctatctcat 20 <210> 28 <211> 18 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 28 acttcaatct ctatctca 18 <210> 29 <211> 19 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 29 cacttcaatc tctatctca 19 <210> 30 <211> 19 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 30 acacttcaat ctctatctc 19 <210> 31 <211> 20 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 31 tacacttcaa tctctatctc 20 <210> 32 <211> 19 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 32 tacacttcaa tctctatct 19 <210> 33 <211> 17 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 33 ctttgtctct ctttact 17 <210> 34 <211> 18 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 34 tatacctttc tttaaccc 18 <210> 35 <211> 16 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 35 tgtttatacc ctttcc 16 <210> 36 <211> 16 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 36 tctcctttat gactcc 16 <210> 37 <211> 17 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 37 cttctccttt atgactc 17 <210> 38 <211> 19 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 38 ccatttattt ccatttatt 19 <210> 39 <211> 20 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 39 ctttccattt atttccattt 20 <210> 40 <211> 20 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 40 tctttccatt tatttccatt 20 <210> 41 <211> 16 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 41 attacccatc cgttct 16 <210> 42 <211> 18 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 42 gcattaggca cattacat 18 <210> 43 <211> 20 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 43 attattattt aaccttccta 20 <210> 44 <211> 20 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 44 acattattat ttaaccttcc 20 <210> 45 <211> 19 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 45 cattattatt taaccttcc 19 <210> 46 <211> 17 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 46 cctctgctta taacttt 17 <210> 47 <211> 17 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 47 ctactatact ttcctct 17 <210> 48 <211> 17 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 48 gttctactat actttcc 17 <210> 49 <211> 18 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 49 cacctgataa cagaccct 18 <210> 50 <211> 16 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 50 cacctgataa cagacc 16 <210> 51 <211> 18 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 51 cccaccaaag gatatatt 18 <210> 52 <211> 18 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 52 accagctaca ggaacctc 18 <210> 53 <211> 19 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 53 ctatatctca ctcctattt 19 <210> 54 <211> 18 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 54 ctatatctca ctcctatt 18 <210> 55 <211> 20 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 55 ctactatatc tcactcctat 20 <210> 56 <211> 19 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 56 tactatatct cactcctat 19 <210> 57 <211> 19 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 57 ctactatatc tcactccta 19 <210> 58 <211> 18 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 58 tactatatct cactccta 18 <210> 59 <211> 18 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 59 ctactatatc tcactcct 18 <210> 60 <211> 17 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 60 ctactatatc tcactcc 17 <210> 61 <211> 17 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 61 cctactatat ctcactc 17 <210> 62 <211> 19 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 62 ctcctactat atctcactc 19 <210> 63 <211> 18 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 63 tcctactata tctcactc 18 <210> 64 <211> 18 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 64 ctcctactat atctcact 18 <210> 65 <211> 19 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 65 tttcctctcc tactatatc 19 <210> 66 <211> 16 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 66 atccatatcc tttcct 16 <210> 67 <211> 17 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 67 catccatatc ctttcct 17 <210> 68 <211> 18 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 68 atcatccata tcctttcc 18 <210> 69 <211> 18 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 69 catcatccat atcctttc 18 <210> 70 <211> 20 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 70 tacatcatcc atatcctttc 20 <210> 71 <211> 18 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 71 acatcatcca tatccttt 18 <210> 72 <211> 17 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 72 catcatccat atccttt 17 <210> 73 <211> 19 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 73 tacatcatcc atatccttt 19 <210> 74 <211> 19 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 74 atacatcatc catatcctt 19 <210> 75 <211> 18 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 75 tacatcatcc atatcctt 18 <210> 76 <211> 20 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 76 tatacatcat ccatatcctt 20 <210> 77 <211> 18 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 77 atacatcatc catatcct 18 <210> 78 <211> 20 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 78 atatacatca tccatatcct 20 <210> 79 <211> 17 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 79 tacatcatcc atatcct 17 <210> 80 <211> 19 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 80 tatacatcat ccatatcct 19 <210> 81 <211> 17 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 81 atacatcatc catatcc 17 <210> 82 <211> 19 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 82 atatacatca tccatatcc 19 <210> 83 <211> 18 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 83 tatacatcat ccatatcc 18 <210> 84 <211> 20 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 84 tatatacatc atccatatcc 20 <210> 85 <211> 16 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 85 gcttcatatt tctcca 16 <210> 86 <211> 17 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 86 catcttgttc tttacct 17 <210> 87 <211> 16 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 87 tatattcacc attgcc 16 <210> 88 <211> 17 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 88 ccttatattc accattg 17 <210> 89 <211> 16 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 89 cctccttata ttcacc 16 <210> 90 <211> 16 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 90 cccttccttt attcaa 16 <210> 91 <211> 17 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 91 ccttactgtt aaatcct 17 <210> 92 <211> 18 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 92 caggcagata acctccaa 18 <210> 93 <211> 18 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 93 cagcaggcag ataacctc 18 <210> 94 <211> 18 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 94 cgaatcttga catacagg 18 <210> 95 <211> 17 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 95 ctcatacttg ctttaat 17 <210> 96 <211> 17 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 96 acatctcata cttgctt 17 <210> 97 <211> 16 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 97 acatctcata cttgct 16 <210> 98 <211> 17 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 98 tacatctcat acttgct 17 <210> 99 <211> 18 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 99 cctacatctc atacttgc 18 <210> 100 <211> 17 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 100 ctacatctca tacttgc 17 <210> 101 <211> 16 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 101 tacatctcat acttgc 16 <210> 102 <211> 17 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 102 cctacatctc atacttg 17 <210> 103 <211> 17 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 103 acctacatct catactt 17 <210> 104 <211> 16 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 104 cctacatctc atactt 16 <210> 105 <211> 18 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 105 tacctacatc tcatactt 18 <210> 106 <211> 19 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 106 ttacctacat ctcatactt 19 <210> 107 <211> 16 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 107 acctacatct catact 16 <210> 108 <211> 17 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 108 tacctacatc tcatact 17 <210> 109 <211> 18 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 109 ttacctacat ctcatact 18 <210> 110 <211> 17 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 110 ttacctacat ctcatac 17 <210> 111 <211> 17 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 111 gttacctaca tctcata 17 <210> 112 <211> 16 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 112 gttacctaca tctcat 16 <210> 113 <211> 18 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 113 atatacccaa aggcacct 18 <210> 114 <211> 20 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 114 tctactcatc ctttaactca 20 <210> 115 <211> 17 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 115 ccttaatctg tatcact 17 <210> 116 <211> 16 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 116 ccatacacag cacata 16 <210> 117 <211> 17 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 117 ctccatacac agcacat 17 <210> 118 <211> 17 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 118 cagaataatt ctcctcc 17 <210> 119 <211> 16 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 119 gtcctacata tatacc 16 <210> 120 <211> 16 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 120 tgcttcctta ctaacc 16 <210> 121 <211> 16 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 121 ccctttgtaa tcatct 16 <210> 122 <211> 17 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 122 tccctttgta atcatct 17 <210> 123 <211> 16 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 123 ctgccatcaa taccat 16 <210> 124 <211> 17 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 124 tcactgccat caatacc 17 <210> 125 <211> 19 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 125 attcttactt tattcctca 19 <210> 126 <211> 17 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 126 tcactttcca gatatca 17 <210> 127 <211> 19 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 127 tccttcaaat tccacatac 19 <210> 128 <211> 17 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 128 acatgtccct ttatatt 17 <210> 129 <211> 16 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 129 acatgtccct ttatat 16 <210> 130 <211> 18 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 130 ccaagaaagg agcaagct 18 <210> 131 <211> 18 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 131 tccaagaaag gagcaagc 18 <210> 132 <211> 17 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 132 ctcatccctc caagaaa 17 <210> 133 <211> 16 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 133 tcatccctcc aagaaa 16 <210> 134 <211> 19 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 134 cacctcccta ttacataaa 19 <210> 135 <211> 18 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 135 cacctcccta ttacataa 18 <210> 136 <211> 16 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 136 cctccctatt acataa 16 <210> 137 <211> 19 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 137 ctaaatcttc caattcata 19 <210> 138 <211> 17 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 138 tatcccttga ttatcct 17 <210> 139 <211> 17 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 139 cctctttgtc aaatact 17 <210> 140 <211> 17 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 140 cagcttattt acctctt 17 <210> 141 <211> 19 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 141 actctttacc tctaacact 19 <210> 142 <211> 20 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 142 ttactcttta cctctaacac 20 <210> 143 <211> 19 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 143 ccaacctaat accttaata 19 <210> 144 <211> 19 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 144 taccaaccta ataccttaa 19 <210> 145 <211> 16 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 145 ccaataccca caaacc 16 <210> 146 <211> 17 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 146 ccattattct actttgt 17 <210> 147 <211> 18 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 147 catttcctta tcttcaca 18 <210> 148 <211> 19 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 148 tcatttcctt atcttcaca 19 <210> 149 <211> 18 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 149 aataattcct catttcct 18 <210> 150 <211> 19 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 150 acaataattc ctcatttcc 19 <210> 151 <211> 16 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 151 tattgaacca attcta 16 <210> 152 <211> 16 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 152 catattgaac caattc 16 <210> 153 <211> 16 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 153 tcatattgaa ccaatt 16 <210> 154 <211> 16 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 154 catcatattg aaccaa 16 <210> 155 <211> 16 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 155 tcatcatatt gaacca 16 <210> 156 <211> 18 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 156 cacaatcaac aacaaata 18 <210> 157 <211> 19 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 157 tacacaatca acaacaaat 19 <210> 158 <211> 16 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 158 ctgtacacaa tcaaca 16 <210> 159 <211> 17 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 159 cactaataat tcacttt 17 <210> 160 <211> 16 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 160 caacattatt gacact 16 <210> 161 <211> 18 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 161 aaactttccc aacattat 18 <210> 162 <211> 17 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 162 tcctatattc tcttaaa 17 <210> 163 <211> 17 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 163 tttcctatat tctctta 17 <210> 164 <211> 17 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 164 caagtttcct atattct 17 <210> 165 <211> 16 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 165 caagtttcct atattc 16 <210> 166 <211> 16 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 166 cattctatct gccaaa 16 <210> 167 <211> 17 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 167 ccattctatc tgccaaa 17 <210> 168 <211> 16 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 168 tatagccatt ctatct 16 <210> 169 <211> 17 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 169 ttatagccat tctatct 17 <210> 170 <211> 19 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 170 atttaaattt ccaaacatt 19 <210> 171 <211> 16 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 171 gctaatttaa atttcc 16 <210> 172 <211> 16 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 172 atcaatatct tctcac 16 <210> 173 <211> 16 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 173 tatcaatatc ttctca 16 <210> 174 <211> 18 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 174 ctacaaattc aatttact 18 <210> 175 <211> 18 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 175 tcttactctg actttcca 18 <210> 176 <211> 17 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 176 tcttactctg actttcc 17 <210> 177 <211> 17 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 177 aaatttccaa acctttc 17 <210> 178 <211> 17 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 178 cttcttgttt atcccaa 17 <210> 179 <211> 16 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 179 ttcttgttta tcccaa 16 <210> 180 <211> 16 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 180 atgcttctaa ctaaca 16 <210> 181 <211> 17 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 181 ctttaatgct tctaact 17 <210> 182 <211> 17 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 182 cctttaatgc ttctaac 17 <210> 183 <211> 16 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 183 ctttaatgct tctaac 16 <210> 184 <211> 17 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 184 ttcctttaat gcttcta 17 <210> 185 <211> 19 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 185 tatacctttc tttaaccct 19 <210> 186 <211> 17 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 186 atacctttct ttaaccc 17 <210> 187 <211> 18 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 187 ttataccttt ctttaacc 18 <210> 188 <211> 18 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 188 tttatacctt tctttaac 18 <210> 189 <211> 17 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 189 tcaagaattc tctcctt 17 <210> 190 <211> 16 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 190 ttcaagaatt ctctcc 16 <210> 191 <211> 16 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 191 cttcaagaat tctctc 16 <210> 192 <211> 16 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 192 tcttcaagaa ttctct 16 <210> 193 <211> 16 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 193 atcttcaaga attctc 16 <210> 194 <211> 16 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 194 tttcttacta tcttca 16 <210> 195 <211> 17 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 195 cctttagcat ttctatt 17 <210> 196 <211> 17 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 196 tcctttagca tttctat 17 <210> 197 <211> 18 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 197 gttctcttta tttcttct 18 <210> 198 <211> 16 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 198 tttactgtca actcct 16 <210> 199 <211> 16 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 199 tttccaatga atctat 16 <210> 200 <211> 17 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 200 cctttccaat gaatcta 17 <210> 201 <211> 16 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 201 ctttccaatg aatcta 16 <210> 202 <211> 16 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 202 cctttccaat gaatct 16 <210> 203 <211> 16 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 203 ttataccctt tccaat 16 <210> 204 <211> 17 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 204 gtttataccc tttccaa 17 <210> 205 <211> 16 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 205 tttataccct ttccaa 16 <210> 206 <211> 16 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 206 gtttataccc tttcca 16 <210> 207 <211> 17 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 207 tgtttatacc ctttcca 17 <210> 208 <211> 18 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 208 actgtttata ccctttcc 18 <210> 209 <211> 17 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 209 actgtttata ccctttc 17 <210> 210 <211> 17 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 210 aactgtttat acccttt 17 <210> 211 <211> 16 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 211 tatgactcca ataatc 16 <210> 212 <211> 17 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 212 ctcctttatg actccaa 17 <210> 213 <211> 16 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 213 ctcctttatg actcca 16 <210> 214 <211> 17 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 214 ccattatttc ttaaata 17 <210> 215 <211> 18 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 215 atttcatatt actaacta 18 <210> 216 <211> 18 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 216 catttcatat tactaact 18 <210> 217 <211> 18 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 217 tcatttcata ttactaac 18 <210> 218 <211> 17 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 218 atcatttcat attacta 17 <210> 219 <211> 18 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 219 ttatcatttc atattact 18 <210> 220 <211> 17 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 220 tgtactttcc tttacca 17 <210> 221 <211> 17 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 221 tatacaccat cattata 17 <210> 222 <211> 17 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 222 ttatacacca tcattat 17 <210> 223 <211> 17 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 223 tatttataca ccatcat 17 <210> 224 <211> 16 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 224 ttatttatac accatc 16 <210> 225 <211> 17 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 225 aattatttat acaccat 17 <210> 226 <211> 16 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 226 catgacactt acataa 16 <210> 227 <211> 16 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 227 agttcactac tattac 16 <210> 228 <211> 16 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 228 ataagcttac ctcata 16 <210> 229 <211> 16 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 229 tataagctta cctcat 16 <210> 230 <211> 16 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 230 atataagctt acctca 16 <210> 231 <211> 17 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 231 cttccctttg ataacat 17 <210> 232 <211> 16 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 232 ttccctttga taacat 16 <210> 233 <211> 17 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 233 ccttcccttt gataaca 17 <210> 234 <211> 16 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 234 cttccctttg ataaca 16 <210> 235 <211> 16 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 235 ccttcccttt gataac 16 <210> 236 <211> 17 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 236 ttgattcaat tccctta 17 <210> 237 <211> 17 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 237 attgattcaa ttccctt 17 <210> 238 <211> 16 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 238 ttgattcaat tccctt 16 <210> 239 <211> 17 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 239 tattgattca attccct 17 <210> 240 <211> 16 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 240 tattgattca attccc 16 <210> 241 <211> 17 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 241 gcacattctt tctatac 17 <210> 242 <211> 16 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 242 gaatttcaac tactat 16 <210> 243 <211> 18 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 243 ccatttattt ccatttat 18 <210> 244 <211> 19 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 244 tttccattta tttccattt 19 <210> 245 <211> 18 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 245 ctttccattt atttccat 18 <210> 246 <211> 18 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 246 tctttccatt tatttcca 18 <210> 247 <211> 18 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 247 atctttccat ttatttcc 18 <210> 248 <211> 16 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 248 ttccatgcaa acttta 16 <210> 249 <211> 16 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 249 cagtttaaat tcacac 16 <210> 250 <211> 16 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 250 ctattccagt ttaaat 16 <210> 251 <211> 16 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 251 tgcaaatacc tcttca 16 <210> 252 <211> 16 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 252 ctaaatagat tccact 16 <210> 253 <211> 16 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 253 tattgatatt tactct 16 <210> 254 <211> 16 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 254 ccttagtatt acaatt 16 <210> 255 <211> 19 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 255 ctattcaata aactaaaca 19 <210> 256 <211> 16 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 256 cagctattca ataaac 16 <210> 257 <211> 16 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 257 tatagaccca aactat 16 <210> 258 <211> 17 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 258 taatcccata catctat 17 <210> 259 <211> 17 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 259 ataatcccat acatcta 17 <210> 260 <211> 16 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 260 atctcaacta ccattt 16 <210> 261 <211> 16 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 261 aatctcaact accatt 16 <210> 262 <211> 16 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 262 acaacttcta tcatac 16 <210> 263 <211> 16 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 263 gaacaacttc tatcat 16 <210> 264 <211> 16 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 264 tgaacaactt ctatca 16 <210> 265 <211> 19 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 265 tacacaaata cttaaatca 19 <210> 266 <211> 16 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 266 ttaagctttc acctat 16 <210> 267 <211> 17 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 267 aaactcttgc atctact 17 <210> 268 <211> 20 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 268 aaatttctca acctaaattt 20 <210> 269 <211> 16 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 269 ccaacataga tcctct 16 <210> 270 <211> 17 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 270 tccaacatag atcctct 17 <210> 271 <211> 17 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 271 ctccaacata gatcctc 17 <210> 272 <211> 16 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 272 tccaacatag atcctc 16 <210> 273 <211> 16 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 273 ctccaacata gatcct 16 <210> 274 <211> 17 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 274 tctccaacat agatcct 17 <210> 275 <211> 16 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 275 attctcaatt gcactt 16 <210> 276 <211> 17 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 276 tattctcaat tgcactt 17 <210> 277 <211> 16 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 277 tcacctaata gcacca 16 <210> 278 <211> 17 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 278 ttcacctaat agcacca 17 <210> 279 <211> 17 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 279 cattattatt taacctt 17 <210> 280 <211> 17 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 280 acattattat ttaacct 17 <210> 281 <211> 17 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 281 tacattatta tttaacc 17 <210> 282 <211> 20 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 282 catttacatt attatttaac 20 <210> 283 <211> 18 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 283 ctcatttaca ttattatt 18 <210> 284 <211> 18 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 284 tatctcattt acattatt 18 <210> 285 <211> 17 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 285 atcattctca acaatta 17 <210> 286 <211> 16 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 286 aagatcattc tcaaca 16 <210> 287 <211> 17 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 287 tctcaaagat cattctc 17 <210> 288 <211> 16 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 288 tctcaaagat cattct 16 <210> 289 <211> 16 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 289 acttaattat acttcc 16 <210> 290 <211> 18 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 290 tacacttaat tatacttc 18 <210> 291 <211> 18 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 291 ttacacttaa ttatactt 18 <210> 292 <211> 18 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 292 tttacactta attatact 18 <210> 293 <211> 17 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 293 ctatttaatt tacactt 17 <210> 294 <211> 18 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 294 tatctattta atttacac 18 <210> 295 <211> 19 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 295 tttatctatt taatttaca 19 <210> 296 <211> 16 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 296 ctctgcttat aacttt 16 <210> 297 <211> 16 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 297 cctctgctta taactt 16 <210> 298 <211> 17 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 298 tcctctgctt ataactt 17 <210> 299 <211> 16 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 299 tcctctgctt ataact 16 <210> 300 <211> 17 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 300 ttcctctgct tataact 17 <210> 301 <211> 17 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 301 tttcctctgc ttataac 17 <210> 302 <211> 16 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 302 tactatactt tcctct 16 <210> 303 <211> 16 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 303 ttctactata ctttcc 16 <210> 304 <211> 17 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 304 agttctacta tactttc 17 <210> 305 <211> 16 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 305 gttctactat actttc 16 <210> 306 <211> 19 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 306 cattatattt aaactatca 19 <210> 307 <211> 19 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 307 cacattatat ttaaactat 19 <210> 308 <211> 19 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 308 acacattata tttaaacta 19 <210> 309 <211> 17 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 309 accacctaag acctcaa 17 <210> 310 <211> 16 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 310 ccacctaaga cctcaa 16 <210> 311 <211> 16 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 311 accacctaag acctca 16 <210> 312 <211> 16 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 312 accttaagta acattt 16 <210> 313 <211> 16 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 313 caccttaagt aacatt 16 <210> 314 <211> 16 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 314 ccaccttaag taacat 16 <210> 315 <211> 16 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 315 accaccttaa gtaaca 16 <210> 316 <211> 16 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 316 ttattaacca ccttaa 16 <210> 317 <211> 16 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 317 cattattaac cacctt 16 <210> 318 <211> 16 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 318 acattattaa ccacct 16 <210> 319 <211> 17 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 319 accaattata cttacaa 17 <210> 320 <211> 17 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 320 aaccaattat acttaca 17 <210> 321 <211> 16 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 321 caaatacaga ttatcc 16 <210> 322 <211> 17 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 322 tttacattcc catcatc 17 <210> 323 <211> 17 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 323 cacacctatt atataat 17 <210> 324 <211> 17 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 324 tcacacctat tatataa 17 <210> 325 <211> 18 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 325 cttcacacct attatata 18 <210> 326 <211> 18 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 326 acttcacacc tattatat 18 <210> 327 <211> 16 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 327 gctcacacta attatt 16 <210> 328 <211> 16 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 328 atgctcacac taatta 16 <210> 329 <211> 16 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 329 aatgctcaca ctaatt 16 <210> 330 <211> 16 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 330 aaactgtaca cctact 16 <210> 331 <211> 17 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 331 gtttccatct actatta 17 <210> 332 <211> 16 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 332 tttccatcta ctatta 16 <210> 333 <211> 16 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 333 tgacataacc atatac 16 <210> 334 <211> 16 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 334 gctcccaaac aactaa 16 <210> 335 <211> 16 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 335 cctcaatact ctactt 16 <210> 336 <211> 17 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 336 gacctcaata ctctact 17 <210> 337 <211> 16 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 337 gacctcaata ctctac 16 <210> 338 <211> 17 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 338 tactaaacat acacata 17 <210> 339 <211> 17 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 339 ctactaaaca tacacat 17 <210> 340 <211> 17 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 340 ttctactaaa catacac 17 <210> 341 <211> 16 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 341 taccaatagt tacctt 16 <210> 342 <211> 17 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 342 cttaccaata gttacct 17 <210> 343 <211> 16 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 343 ttaccaatag ttacct 16 <210> 344 <211> 16 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 344 cttaccaata gttacc 16 <210> 345 <211> 17 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 345 tcttaccaat agttacc 17 <210> 346 <211> 17 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 346 tcaaagcaca ccaccac 17 <210> 347 <211> 17 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 347 attcaaagca caccacc 17 <210> 348 <211> 16 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 348 agactaatcc tcttaa 16 <210> 349 <211> 16 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 349 tagactaatc ctctta 16 <210> 350 <211> 18 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 350 cccatttcta acatttac 18 <210> 351 <211> 16 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 351 acccatttct aacatt 16 <210> 352 <211> 16 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 352 aacccatttc taacat 16 <210> 353 <211> 16 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 353 cctcaacttc accaat 16 <210> 354 <211> 16 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 354 actgatttcc ttaaac 16 <210> 355 <211> 17 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 355 cactgatttc cttaaac 17 <210> 356 <211> 17 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 356 ccactgattt ccttaaa 17 <210> 357 <211> 16 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 357 accactgatt tcctta 16 <210> 358 <211> 16 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 358 caccactgat ttcctt 16 <210> 359 <211> 16 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 359 ctctgcaata caccaa 16 <210> 360 <211> 16 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 360 actctgcaat acacca 16 <210> 361 <211> 17 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 361 tactctgcaa tacacca 17 <210> 362 <211> 16 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 362 tactctgcaa tacacc 16 <210> 363 <211> 17 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 363 ttactctgca atacacc 17 <210> 364 <211> 16 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 364 ttactctgca atacac 16 <210> 365 <211> 17 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 365 tttactctgc aatacac 17 <210> 366 <211> 17 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 366 ctttactctg caataca 17 <210> 367 <211> 16 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 367 tttactctgc aataca 16 <210> 368 <211> 17 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 368 gaccacactt tctacca 17 <210> 369 <211> 16 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 369 gaccacactt tctacc 16 <210> 370 <211> 16 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 370 aagaaacacc cttcca 16 <210> 371 <211> 17 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 371 atctgctaca tattctt 17 <210> 372 <211> 16 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 372 atctgctaca tattct 16 <210> 373 <211> 17 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 373 catctgctac atattct 17 <210> 374 <211> 16 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 374 catctgctac atattc 16 <210> 375 <211> 16 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 375 ttcaacccta atcact 16 <210> 376 <211> 16 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 376 attcaaccct aatcac 16 <210> 377 <211> 16 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 377 cattcaaccc taatca 16 <210> 378 <211> 17 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 378 gcattcaacc ctaatca 17 <210> 379 <211> 17 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 379 agcattcaac cctaatc 17 <210> 380 <211> 16 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 380 gcattcaacc ctaatc 16 <210> 381 <211> 16 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 381 agcattcaac cctaat 16 <210> 382 <211> 17 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 382 cagcattcaa ccctaat 17 <210> 383 <211> 16 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 383 ttaaatccag cattca 16 <210> 384 <211> 16 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 384 ctccatattt aaatcc 16 <210> 385 <211> 17 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 385 gctccatatt taaatcc 17 <210> 386 <211> 16 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 386 gctccatatt taaatc 16 <210> 387 <211> 16 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 387 agctccatat ttaaat 16 <210> 388 <211> 16 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 388 taagctccat atttaa 16 <210> 389 <211> 17 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 389 cctaagctcc atattta 17 <210> 390 <211> 16 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 390 ctaagctcca tattta 16 <210> 391 <211> 16 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 391 cctaagctcc atattt 16 <210> 392 <211> 16 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 392 tctaccctaa attccc 16 <210> 393 <211> 16 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 393 cacatcttgt atacaa 16 <210> 394 <211> 16 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 394 acacatcttg tataca 16 <210> 395 <211> 17 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 395 ctacacatct tgtatac 17 <210> 396 <211> 16 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 396 tacacatctt gtatac 16 <210> 397 <211> 16 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 397 cttgactaca catctt 16 <210> 398 <211> 16 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 398 ctctacaaca gtccca 16 <210> 399 <211> 17 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 399 tctctacaac agtccca 17 <210> 400 <211> 18 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 400 ataacattac tcttaaca 18 <210> 401 <211> 17 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 401 tttgacattc catctcc 17 <210> 402 <211> 17 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 402 ctttgacatt ccatctc 17 <210> 403 <211> 18 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 403 tctttgacat tccatctc 18 <210> 404 <211> 16 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 404 tttgacattc catctc 16 <210> 405 <211> 17 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 405 atctttgaca ttccatc 17 <210> 406 <211> 17 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 406 tatctttgac attccat 17 <210> 407 <211> 17 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 407 tactatcttt gacattc 17 <210> 408 <211> 16 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 408 tactatcttt gacatt 16 <210> 409 <211> 16 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 409 ctgtatacac catccc 16 <210> 410 <211> 16 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 410 tctgtataca ccatcc 16 <210> 411 <211> 17 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 411 tttctgactc cctatcc 17 <210> 412 <211> 17 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 412 cctatgttaa tactttc 17 <210> 413 <211> 16 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 413 ctatgttaat actttc 16 <210> 414 <211> 16 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 414 cctatgttaa tacttt 16 <210> 415 <211> 16 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 415 tcctatgtta atactt 16 <210> 416 <211> 16 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 416 atcctatgtt aatact 16 <210> 417 <211> 17 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 417 atttcattaa gtcaccc 17 <210> 418 <211> 16 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 418 atttcattaa gtcacc 16 <210> 419 <211> 17 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 419 ctctcctcaa gatcaac 17 <210> 420 <211> 16 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 420 ctctcctcaa gatcaa 16 <210> 421 <211> 16 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 421 ccatacagta tataca 16 <210> 422 <211> 16 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 422 caactattat cttctt 16 <210> 423 <211> 16 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 423 acaactatta tcttct 16 <210> 424 <211> 17 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 424 ttgcttccaa tttattt 17 <210> 425 <211> 17 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 425 atctcatgac cacctaa 17 <210> 426 <211> 16 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 426 tctcatgacc acctaa 16 <210> 427 <211> 16 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 427 atctcatgac caccta 16 <210> 428 <211> 17 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 428 tatctcatga ccaccta 17 <210> 429 <211> 17 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 429 tttatctcat gaccacc 17 <210> 430 <211> 16 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 430 tttatctcat gaccac 16 <210> 431 <211> 16 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 431 attcttaccg tcttta 16 <210> 432 <211> 17 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 432 tattcttacc gtcttta 17 <210> 433 <211> 16 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 433 tattcttacc gtcttt 16 <210> 434 <211> 17 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 434 ttattcttac cgtcttt 17 <210> 435 <211> 16 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 435 atctgatctc acacat 16 <210> 436 <211> 17 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 436 catctgatct cacacat 17 <210> 437 <211> 17 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 437 acttccagat ttctaca 17 <210> 438 <211> 16 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 438 tttatgttta cttcat 16 <210> 439 <211> 17 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 439 taaagatccc atcactc 17 <210> 440 <211> 16 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 440 taaagatccc atcact 16 <210> 441 <211> 17 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 441 cctaaagatc ccatcac 17 <210> 442 <211> 16 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 442 atcatcagtt acatca 16 <210> 443 <211> 17 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 443 actctcactg taacttt 17 <210> 444 <211> 17 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 444 aactctcact gtaactt 17 <210> 445 <211> 16 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 445 actctcactg taactt 16 <210> 446 <211> 16 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 446 aactctcact gtaact 16 <210> 447 <211> 17 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 447 caactctcac tgtaact 17 <210> 448 <211> 17 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 448 cctttcatta acattta 17 <210> 449 <211> 18 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 449 ttcctttcat taacattt 18 <210> 450 <211> 16 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 450 taatcctatt ccaact 16 <210> 451 <211> 16 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 451 ctaatcctat tccaac 16 <210> 452 <211> 16 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 452 ctctaatcct attcca 16 <210> 453 <211> 16 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 453 tctctaatcc tattcc 16 <210> 454 <211> 17 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 454 ttgtctctaa tcctatt 17 <210> 455 <211> 16 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 455 ttgtctctaa tcctat 16 <210> 456 <211> 16 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 456 tctttaagct tcccac 16 <210> 457 <211> 16 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 457 aaactaccct gcacaa 16 <210> 458 <211> 16 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 458 ccatgctaca taaacc 16 <210> 459 <211> 16 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 459 tccatgctac ataaac 16 <210> 460 <211> 16 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 460 actcctaaga attaca 16 <210> 461 <211> 16 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 461 gaaactatta ctccta 16 <210> 462 <211> 16 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 462 tgaaactatt actcct 16 <210> 463 <211> 16 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 463 atgaaactat tactcc 16 <210> 464 <211> 16 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 464 aacaactcat gccaca 16 <210> 465 <211> 16 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 465 aaatattgcc accatt 16 <210> 466 <211> 17 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 466 gttacatatt ctttcac 17 <210> 467 <211> 16 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 467 tcatacttgc tttaat 16 <210> 468 <211> 16 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 468 atcctgataa ttaact 16 <210> 469 <211> 16 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 469 ccttaatctg tatcac 16 <210> 470 <211> 16 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 470 atacacagca catatt 16 <210> 471 <211> 16 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 471 tcagaataat tctcct 16 <210> 472 <211> 17 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 472 tcttcagctt tctaaat 17 <210> 473 <211> 17 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 473 agtccttcct ttaacca 17 <210> 474 <211> 17 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 474 tagtccttcc tttaacc 17 <210> 475 <211> 16 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 475 tttaaccttg cttata 16 <210> 476 <211> 16 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 476 atccctttgt aatcat 16 <210> 477 <211> 17 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 477 cttgcatttc taattac 17 <210> 478 <211> 17 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 478 cttgtcaaat catttct 17 <210> 479 <211> 16 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 479 ccatctaatg attatt 16 <210> 480 <211> 16 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 480 tatcagttat ccaata 16 <210> 481 <211> 16 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 481 tcactgccat caatac 16 <210> 482 <211> 16 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 482 tgtcatctac aaatca 16 <210> 483 <211> 16 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 483 ctctttagat tcatcc 16 <210> 484 <211> 16 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 484 actctttaga ttcatc 16 <210> 485 <211> 16 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 485 caactctatg actacc 16 <210> 486 <211> 16 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 486 acctgtaata cttctt 16 <210> 487 <211> 17 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 487 gaattcttta ttcctcc 17 <210> 488 <211> 16 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 488 atctgaatca aacctt 16 <210> 489 <211> 17 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 489 actttactgc cataatc 17 <210> 490 <211> 16 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 490 ttactcttag caacct 16 <210> 491 <211> 17 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 491 caccagtatt tcttctt 17 <210> 492 <211> 17 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 492 ttcaccagta tttcttc 17 <210> 493 <211> 16 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 493 ccaaataagc aaactc 16 <210> 494 <211> 16 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 494 cccaaataag caaact 16 <210> 495 <211> 16 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 495 gactacattc tcaata 16 <210> 496 <211> 17 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 496 ttgtcaatct ttattct 17 <210> 497 <211> 16 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 497 agcttaccaa atattc 16 <210> 498 <211> 16 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 498 ttacacatgt atatcc 16 <210> 499 <211> 16 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 499 atcctgttaa taccat 16 <210> 500 <211> 16 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 500 ttcttagtca cacaca 16 <210> 501 <211> 17 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 501 ttctgtttcc atttaca 17 <210> 502 <211> 17 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 502 tctatatcaa gttcctt 17 <210> 503 <211> 16 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 503 attcagttac caacta 16 <210> 504 <211> 16 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 504 gcttctactt aaatat 16 <210> 505 <211> 16 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 505 ccctcaaagt aatttc 16 <210> 506 <211> 16 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 506 aacatgtaat ttccat 16 <210> 507 <211> 16 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 507 ccagactcca atattt 16 <210> 508 <211> 17 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 508 cttagacttc acctttc 17 <210> 509 <211> 16 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 509 ctgcttaatt atatca 16 <210> 510 <211> 17 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 510 aaattgtcta ccttcct 17 <210> 511 <211> 16 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 511 cacttagaat atccct 16 <210> 512 <211> 16 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 512 atccaaagtt tctttc 16 <210> 513 <211> 16 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 513 atatttgtca cctaac 16 <210> 514 <211> 16 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 514 ctattctcag tattat 16 <210> 515 <211> 16 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 515 ccattcaatg atcact 16 <210> 516 <211> 16 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 516 cactagtact cttatt 16 <210> 517 <211> 16 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 517 gccacaacat ctattt 16 <210> 518 <211> 16 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 518 agcacatata ccatca 16 <210> 519 <211> 17 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 519 gtcatctaac ttcttac 17 <210> 520 <211> 17 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 520 tgtcatctaa cttctta 17 <210> 521 <211> 16 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 521 cccttatagt tattaa 16 <210> 522 <211> 16 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 522 tccatagaat tcttca 16 <210> 523 <211> 16 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 523 ttgattccac cattaa 16 <210> 524 <211> 16 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 524 cagccataaa ctatat 16 <210> 525 <211> 16 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 525 tatgacttat tccata 16 <210> 526 <211> 16 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 526 gttaacctat atttca 16 <210> 527 <211> 17 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 527 tgtctattct cttcatt 17 <210> 528 <211> 17 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 528 ttactctttg atttcat 17 <210> 529 <211> 16 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 529 gataattcca aatccc 16 <210> 530 <211> 17 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 530 tcttatcctt gaatttc 17 <210> 531 <211> 17 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 531 atatcccttg attatcc 17 <210> 532 <211> 16 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 532 ttagtatacc ctttat 16 <210> 533 <211> 16 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 533 ctctttgtca aatact 16 <210> 534 <211> 17 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 534 ccaaactgtc ttctaat 17 <210> 535 <211> 17 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 535 tccaaactgt cttctaa 17 <210> 536 <211> 16 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 536 ccagcatatt atatac 16 <210> 537 <211> 16 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 537 tccagcatat tatata 16 <210> 538 <211> 17 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 538 tcattgaaca actcttc 17 <210> 539 <211> 17 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 539 ctgccatctt tatttat 17 <210> 540 <211> 17 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 540 tgaaacattc ttcccac 17 <210> 541 <211> 16 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 541 tttattagat tactcc 16 <210> 542 <211> 17 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 542 ttccagctta tttacct 17 <210> 543 <211> 16 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 543 agcatcatat aaacct 16 <210> 544 <211> 16 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 544 gtacttacac atctat 16 <210> 545 <211> 16 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 545 tgtacttaca catcta 16 <210> 546 <211> 17 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 546 atttctctat gtcacat 17 <210> 547 <211> 16 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 547 caaacctacg tctctc 16 <210> 548 <211> 17 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 548 gtatttactc tttacct 17 <210> 549 <211> 16 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 549 ctaatgcaat aaccca 16 <210> 550 <211> 16 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 550 actaatgcaa taaccc 16 <210> 551 <211> 16 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 551 agctctaaac cttcaa 16 <210> 552 <211> 16 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 552 tatttgtcac caaacc 16 <210> 553 <211> 16 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 553 ctcagacatc tcaata 16 <210> 554 <211> 17 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 554 tctcagcttc ttcaaat 17 <210> 555 <211> 16 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 555 gccaataccc acaaac 16 <210> 556 <211> 16 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 556 cctctgacaa ccatta 16 <210> 557 <211> 16 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 557 cagataactc taaacc 16 <210> 558 <211> 17 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 558 ctaactgttt ctcaatt 17 <210> 559 <211> 16 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 559 ccaagataat catcat 16 <210> 560 <211> 16 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 560 tacatattgt acttct 16 <210> 561 <211> 16 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 561 tagcctactt taatat 16 <210> 562 <211> 16 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 562 catttacaag cacata 16 <210> 563 <211> 16 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 563 ttattctgac acactt 16 <210> 564 <211> 16 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 564 tacattgaca cctaat 16 <210> 565 <211> 16 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 565 tttacattga caccta 16 <210> 566 <211> 16 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 566 tgtatataac tattcc 16 <210> 567 <211> 17 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 567 gaatcttcta attccac 17 <210> 568 <211> 16 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 568 tgctcactaa ctacac 16 <210> 569 <211> 17 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 569 tgctaccatc attacct 17 <210> 570 <211> 20 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 570 tttatcaata tcttctcact 20 <210> 571 <211> 19 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 571 tttatcaata tcttctcac 19 <210> 572 <211> 18 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 572 tttatcaata tcttctca 18 <210> 573 <211> 20 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 573 tatacctttc tttaaccctt 20 <210> 574 <211> 20 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 574 ttataccttt ctttaaccct 20 <210> 575 <211> 20 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 575 tttatacctt tctttaaccc 20 <210> 576 <211> 20 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 576 ttttatacct ttctttaacc 20 <210> 577 <211> 20 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 577 tttttatacc tttctttaac 20 <210> 578 <211> 20 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 578 ttttttctta ctatcttcaa 20 <210> 579 <211> 20 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 579 tttttttctt actatcttca 20 <210> 580 <211> 20 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 580 atttttttct tactatcttc 20 <210> 581 <211> 20 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 581 aatttttttc ttactatctt 20 <210> 582 <211> 18 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 582 gtttataccc tttccaat 18 <210> 583 <211> 18 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 583 tgtttatacc ctttccaa 18 <210> 584 <211> 18 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 584 ctgtttatac cctttcca 18 <210> 585 <211> 20 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 585 aattatttat acaccatcat 20 <210> 586 <211> 20 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 586 aaattattta tacaccatca 20 <210> 587 <211> 20 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 587 aaaattattt atacaccatc 20 <210> 588 <211> 20 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 588 taaaattatt tatacaccat 20 <210> 589 <211> 19 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 589 taaaattatt tatacacca 19 <210> 590 <211> 17 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 590 atattgattc aattccc 17 <210> 591 <211> 19 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 591 gcacattctt tctatacct 19 <210> 592 <211> 18 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 592 gcacattctt tctatacc 18 <210> 593 <211> 19 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 593 ttatttccat ttattttca 19 <210> 594 <211> 20 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 594 tttatttcca tttattttca 20 <210> 595 <211> 20 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 595 atttatttcc atttattttc 20 <210> 596 <211> 19 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 596 tttatttcca tttattttc 19 <210> 597 <211> 20 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 597 ccatttattt ccatttattt 20 <210> 598 <211> 20 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 598 tccatttatt tccatttatt 20 <210> 599 <211> 19 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 599 tccatttatt tccatttat 19 <210> 600 <211> 20 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 600 ttccatttat ttccatttat 20 <210> 601 <211> 20 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 601 tttccattta tttccattta 20 <210> 602 <211> 19 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 602 ctttccattt atttccatt 19 <210> 603 <211> 20 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 603 atctttccat ttatttccat 20 <210> 604 <211> 19 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 604 tctttccatt tatttccat 19 <210> 605 <211> 19 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 605 atctttccat ttatttcca 19 <210> 606 <211> 20 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 606 tatctttcca tttatttcca 20 <210> 607 <211> 19 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 607 tatctttcca tttatttcc 19 <210> 608 <211> 20 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 608 aaatctcaac taccattttt 20 <210> 609 <211> 20 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 609 aaaatctcaa ctaccatttt 20 <210> 610 <211> 19 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 610 aaaatctcaa ctaccattt 19 <210> 611 <211> 19 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 611 gaaaatctca actaccatt 19 <210> 612 <211> 19 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 612 tgaaaatctc aactaccat 19 <210> 613 <211> 19 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 613 atcattctca acaattaaa 19 <210> 614 <211> 18 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 614 atcattctca acaattaa 18 <210> 615 <211> 19 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 615 gatcattctc aacaattaa 19 <210> 616 <211> 19 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 616 agatcattct caacaatta 19 <210> 617 <211> 18 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 617 gatcattctc aacaatta 18 <210> 618 <211> 18 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 618 agatcattct caacaatt 18 <210> 619 <211> 17 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 619 gatcattctc aacaatt 17 <210> 620 <211> 18 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 620 aagatcattc tcaacaat 18 <210> 621 <211> 18 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 621 aaagatcatt ctcaacaa 18 <210> 622 <211> 18 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 622 caaagatcat tctcaaca 18 <210> 623 <211> 17 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 623 caaagatcat tctcaac 17 <210> 624 <211> 17 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 624 ctcaaagatc attctca 17 <210> 625 <211> 20 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 625 tacacttaat tatacttcca 20 <210> 626 <211> 20 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 626 ttacacttaa ttatacttcc 20 <210> 627 <211> 20 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 627 tttacactta attatacttc 20 <210> 628 <211> 20 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 628 atttacactt aattatactt 20 <210> 629 <211> 19 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 629 ttctactata ctttcctct 19 <210> 630 <211> 19 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 630 gttctactat actttcctc 19 <210> 631 <211> 18 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 631 gttctactat actttcct 18 <210> 632 <211> 18 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 632 agttctacta tactttcc 18 <210> 633 <211> 20 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 633 caacattatt aaccacctta 20 <210> 634 <211> 19 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 634 caacattatt aaccacctt 19 <210> 635 <211> 19 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 635 gcaacattat taaccacct 19 <210> 636 <211> 19 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 636 agcaacatta ttaaccacc 19 <210> 637 <211> 18 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 637 agcaacatta ttaaccac 18 <210> 638 <211> 19 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 638 gtttccatct actattaat 19 <210> 639 <211> 18 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 639 gtttccatct actattaa 18 <210> 640 <211> 18 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 640 tgtttccatc tactatta 18 <210> 641 <211> 17 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 641 actctgcaat acaccaa 17 <210> 642 <211> 17 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 642 ctgtatacac catccca 17 <210> 643 <211> 18 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 643 tctgtataca ccatccca 18 <210> 644 <211> 17 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 644 tctgtataca ccatccc 17 <210> 645 <211> 18 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 645 ttctgtatac accatccc 18 <210> 646 <211> 17 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 646 ttctgtatac accatcc 17 <210> 647 <211> 16 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 647 agcttttaac cagagt 16 <210> 648 <211> 17 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 648 agcttttaac cagagtg 17 <210> 649 <211> 18 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 649 agcttttaac cagagtgg 18 <210> 650 <211> 19 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 650 agcttttaac cagagtggc 19 <210> 651 <211> 20 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 651 agcttttaac cagagtggca 20 <210> 652 <211> 17 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 652 cagcttttaa ccagagt 17 <210> 653 <211> 18 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 653 cagcttttaa ccagagtg 18 <210> 654 <211> 19 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 654 cagcttttaa ccagagtgg 19 <210> 655 <211> 20 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 655 cagcttttaa ccagagtggc 20 <210> 656 <211> 15 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 656 cttttaacca gagtg 15 <210> 657 <211> 16 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 657 cttttaacca gagtgg 16 <210> 658 <211> 17 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 658 cttttaacca gagtggc 17 <210> 659 <211> 18 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 659 cttttaacca gagtggca 18 <210> 660 <211> 19 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 660 cttttaacca gagtggcat 19 <210> 661 <211> 20 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 661 cttttaacca gagtggcatc 20 <210> 662 <211> 15 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 662 gcttttaacc agagt 15 <210> 663 <211> 16 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 663 gcttttaacc agagtg 16 <210> 664 <211> 17 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 664 gcttttaacc agagtgg 17 <210> 665 <211> 18 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 665 gcttttaacc agagtggc 18 <210> 666 <211> 19 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 666 gcttttaacc agagtggca 19 <210> 667 <211> 20 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 667 gcttttaacc agagtggcat 20 <210> 668 <211> 18 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 668 tcagctttta accagagt 18 <210> 669 <211> 19 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 669 tcagctttta accagagtg 19 <210> 670 <211> 20 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 670 tcagctttta accagagtgg 20 <210> 671 <211> 19 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 671 ttcagctttt aaccagagt 19 <210> 672 <211> 20 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 672 ttcagctttt aaccagagtg 20 <210> 673 <211> 20 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 673 tttcagcttt taaccagagt 20 <210> 674 <211> 16 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 674 ttttaaccag agtggc 16 <210> 675 <211> 17 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 675 ttttaaccag agtggca 17 <210> 676 <211> 18 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 676 ttttaaccag agtggcat 18 <210> 677 <211> 19 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 677 ttttaaccag agtggcatc 19 <210> 678 <211> 20 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 678 ttttaaccag agtggcatcc 20 <210> 679 <211> 17 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 679 atcaatatct tctcact 17 <210> 680 <211> 18 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 680 tatcaatatc ttctcact 18 <210> 681 <211> 17 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 681 tatcaatatc ttctcac 17 <210> 682 <211> 18 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 682 ttatcaatat cttctcac 18 <210> 683 <211> 19 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 683 ttatcaatat cttctcact 19 <210> 684 <211> 18 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 684 acctttcttt aacccttt 18 <210> 685 <211> 19 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 685 tacctttctt taacccttt 19 <210> 686 <211> 17 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 686 atacctttct ttaaccc 17 <210> 687 <211> 19 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 687 atacctttct ttaaccctt 19 <210> 688 <211> 20 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 688 atacctttct ttaacccttt 20 <210> 689 <211> 18 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 689 atacctttct ttaaccct 18 <210> 690 <211> 19 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 690 tatacctttc tttaaccct 19 <210> 691 <211> 17 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 691 ttataccttt ctttaac 17 <210> 692 <211> 19 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 692 ttataccttt ctttaaccc 19 <210> 693 <211> 18 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 693 ttataccttt ctttaacc 18 <210> 694 <211> 19 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 694 tttatacctt tctttaacc 19 <210> 695 <211> 18 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 695 tttatacctt tctttaac 18 <210> 696 <211> 19 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 696 ttttatacct ttctttaac 19 <210> 697 <211> 17 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 697 tgtactttcc tttacca 17 <210> 698 <211> 17 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 698 ttatacacca tcattat 17 <210> 699 <211> 18 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 699 ttatacacca tcattata 18 <210> 700 <211> 18 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 700 tttatacacc atcattat 18 <210> 701 <211> 19 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 701 tttatacacc atcattata 19 <210> 702 <211> 19 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 702 atttatacac catcattat 19 <210> 703 <211> 20 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 703 atttatacac catcattata 20 <210> 704 <211> 19 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 704 tatttataca ccatcatta 19 <210> 705 <211> 20 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 705 tatttataca ccatcattat 20 <210> 706 <211> 20 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 706 ttatttatac accatcatta 20 <210> 707 <211> 19 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 707 attatttata caccatcat 19 <210> 708 <211> 18 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 708 attatttata caccatca 18 <210> 709 <211> 20 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 709 attatttata caccatcatt 20 <210> 710 <211> 17 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 710 attatttata caccatc 17 <210> 711 <211> 18 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 711 aattatttat acaccatc 18 <210> 712 <211> 19 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 712 aattatttat acaccatca 19 <210> 713 <211> 19 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 713 aaattattta tacaccatc 19 <210> 714 <211> 18 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 714 aaattattta tacaccat 18 <210> 715 <211> 19 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 715 aaaattattt atacaccat 19 <210> 716 <211> 18 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 716 taaaattatt tatacacc 18 <210> 717 <211> 19 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 717 gtaaaattat ttatacacc 19 <210> 718 <211> 18 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 718 gtaaaattat ttatacac 18 <210> 719 <211> 16 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 719 gagtatatta cctcca 16 <210> 720 <211> 17 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 720 cttttctata atctcac 17 <210> 721 <211> 18 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 721 cttttctata atctcaca 18 <210> 722 <211> 19 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 722 tcttttctat aatctcaca 19 <210> 723 <211> 18 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 723 tcttttctat aatctcac 18 <210> 724 <211> 20 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 724 atcttttcta taatctcaca 20 <210> 725 <211> 19 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 725 atcttttcta taatctcac 19 <210> 726 <211> 18 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 726 atcttttcta taatctca 18 <210> 727 <211> 20 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 727 catcttttct ataatctcac 20 <210> 728 <211> 19 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 728 catcttttct ataatctca 19 <210> 729 <211> 20 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 729 tcatcttttc tataatctca 20 <210> 730 <211> 19 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 730 tcatcttttc tataatctc 19 <210> 731 <211> 18 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 731 gtcatctttt ctataatc 18 <210> 732 <211> 18 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 732 tgtcatcttt tctataat 18 <210> 733 <211> 17 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 733 acttaattat acttcca 17 <210> 734 <211> 17 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 734 cacttaatta tacttcc 17 <210> 735 <211> 18 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 735 cacttaatta tacttcca 18 <210> 736 <211> 19 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 736 acacttaatt atacttcca 19 <210> 737 <211> 18 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 737 acacttaatt atacttcc 18 <210> 738 <211> 17 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 738 acacttaatt atacttc 17 <210> 739 <211> 19 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 739 tacacttaat tatacttcc 19 <210> 740 <211> 18 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 740 tacacttaat tatacttc 18 <210> 741 <211> 19 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 741 ttacacttaa ttatacttc 19 <210> 742 <211> 18 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 742 ttacacttaa ttatactt 18 <210> 743 <211> 19 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 743 tttacactta attatactt 19 <210> 744 <211> 18 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 744 tttacactta attatact 18 <210> 745 <211> 19 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 745 atttacactt aattatact 19 <210> 746 <211> 18 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 746 atttacactt aattatac 18 <210> 747 <211> 19 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 747 aatttacact taattatac 19 <210> 748 <211> 20 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 748 aatttacact taattatact 20 <210> 749 <211> 20 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 749 taatttacac ttaattatac 20 <210> 750 <211> 18 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 750 taatttacac ttaattat 18 <210> 751 <211> 19 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 751 taatttacac ttaattata 19 <210> 752 <211> 20 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 752 ttaatttaca cttaattata 20 <210> 753 <211> 19 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 753 ttaatttaca cttaattat 19 <210> 754 <211> 19 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 754 tttaatttac acttaatta 19 <210> 755 <211> 20 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 755 tttaatttac acttaattat 20 <210> 756 <211> 20 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 756 atttaattta cacttaatta 20 <210> 757 <211> 19 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 757 atttaattta cacttaatt 19 <210> 758 <211> 19 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 758 tatttaattt acacttaat 19 <210> 759 <211> 20 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 759 tatttaattt acacttaatt 20 <210> 760 <211> 17 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 760 ctatttaatt tacactt 17 <210> 761 <211> 19 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 761 ctatttaatt tacacttaa 19 <210> 762 <211> 18 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 762 ctatttaatt tacactta 18 <210> 763 <211> 20 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 763 ctatttaatt tacacttaat 20 <210> 764 <211> 19 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 764 tctatttaat ttacactta 19 <210> 765 <211> 18 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 765 tctatttaat ttacactt 18 <210> 766 <211> 20 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 766 tctatttaat ttacacttaa 20 <210> 767 <211> 19 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 767 atctatttaa tttacactt 19 <210> 768 <211> 20 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 768 atctatttaa tttacactta 20 <210> 769 <211> 20 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 769 tatctattta atttacactt 20 <210> 770 <211> 19 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 770 tatctattta atttacact 19 <210> 771 <211> 20 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 771 ttatctattt aatttacact 20 <210> 772 <211> 19 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 772 tttatctatt taatttaca 19 <210> 773 <211> 19 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 773 ttttatctat ttaatttac 19 <210> 774 <211> 20 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 774 ttttatctat ttaatttaca 20 <210> 775 <211> 19 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 775 cttttatcta tttaattta 19 <210> 776 <211> 20 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 776 cttttatcta tttaatttac 20 <210> 777 <211> 19 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 777 acttttatct atttaattt 19 <210> 778 <211> 20 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 778 acttttatct atttaattta 20 <210> 779 <211> 18 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 779 acttttatct atttaatt 18 <210> 780 <211> 19 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 780 aacttttatc tatttaatt 19 <210> 781 <211> 18 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 781 aacttttatc tatttaat 18 <210> 782 <211> 20 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 782 aacttttatc tatttaattt 20 <210> 783 <211> 19 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 783 taacttttat ctatttaat 19 <210> 784 <211> 20 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 784 taacttttat ctatttaatt 20 <210> 785 <211> 18 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 785 taacttttat ctatttaa 18 <210> 786 <211> 19 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 786 ataactttta tctatttaa 19 <210> 787 <211> 20 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 787 ataactttta tctatttaat 20 <210> 788 <211> 19 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 788 tataactttt atctattta 19 <210> 789 <211> 20 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 789 tataactttt atctatttaa 20 <210> 790 <211> 19 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 790 ttataacttt tatctattt 19 <210> 791 <211> 18 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 791 ttataacttt tatctatt 18 <210> 792 <211> 20 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 792 ttataacttt tatctattta 20 <210> 793 <211> 19 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 793 cttataactt ttatctatt 19 <210> 794 <211> 18 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 794 cttataactt ttatctat 18 <210> 795 <211> 20 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 795 cttataactt ttatctattt 20 <210> 796 <211> 17 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 796 cttataactt ttatcta 17 <210> 797 <211> 18 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 797 gcttataact tttatcta 18 <210> 798 <211> 17 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 798 gcttataact tttatct 17 <210> 799 <211> 17 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 799 tgcttataac ttttatc 17 <210> 800 <211> 18 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 800 tgcttataac ttttatct 18 <210> 801 <211> 18 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 801 ctgcttataa cttttatc 18 <210> 802 <211> 17 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 802 ctctgcttat aactttt 17 <210> 803 <211> 17 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 803 cctctgctta taacttt 17 <210> 804 <211> 17 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 804 ctactatact ttcctct 17 <210> 805 <211> 18 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 805 tctactatac tttcctct 18 <210> 806 <211> 17 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 806 ttctactata ctttcct 17 <210> 807 <211> 18 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 807 ttctactata ctttcctc 18 <210> 808 <211> 18 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 808 tttccatcta ctattaat 18 <210> 809 <211> 17 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 809 tttccatcta ctattaa 17 <210> 810 <211> 17 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 810 gtttccatct actatta 17 <210> 811 <211> 18 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 811 aatacaaaat catcttac 18 <210> 812 <211> 19 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 812 aatacaaaat catcttaca 19 <210> 813 <211> 18 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 813 taatacaaaa tcatctta 18 <210> 814 <211> 19 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 814 taatacaaaa tcatcttac 19 <210> 815 <211> 20 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 815 taatacaaaa tcatcttaca 20 <210> 816 <211> 18 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 816 tctgtataca ccatccca 18 <210> 817 <211> 17 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 817 ttctgactcc ctatcca 17 <210> 818 <211> 17 <212> DNA <213> Artificial Sequence <220> <223> oligonucleotide motif <400> 818 tttctgactc cctatcc 17 <210> 819 <211> 15 <212> DNA <213> Artificial sequence <220> <223> Control oligonucleotide <220> <221> beta-oxy-LNA nucloside <222> (1)..(3) <220> <221> phosphorothiate Internucleoside linkages <222> (1)..(15) <220> <221> beta-oxy-LNA nucloside <222> (13)..(15) <400> 819 cgaaccactg aacaa 15 <210> 820 <211> 16 <212> DNA <213> Artificial sequence <220> <223> Control oligonucleotide <220> <221> beta-oxy-LNA nucloside <222> (1)..(3) <220> <221> phosphorothiate Internucleoside linkages <222> (1)..(16) <220> <221> beta-oxy-LNA nucloside <222> (14)..(16) <400> 820 cgaaccactg aacaaa 16 <210> 821 <211> 13 <212> DNA <213> Artificial sequence <220> <223> Control oligonucleotide <220> <221> beta-oxy-LNA nucloside <222> (1)..(3) <220> <221> phosphorothiate Internucleoside linkages <222> (1)..(13) <220> <221> beta-oxy-LNA nucloside <222> (12)..(13) <400> 821 cgaagtgcac acg 13 <210> 822 <211> 14 <212> DNA <213> Artificial sequence <220> <223> Control oligonucleotide <220> <221> beta-oxy-LNA nucloside <222> (1)..(3) <220> <221> phosphorothiate Internucleoside linkages <222> (1)..(14) <220> <221> beta-oxy-LNA nucloside <222> (12)..(14) <400> 822 gcgtaaagag aggt 14 <210> 823 <211> 16 <212> DNA <213> Artificial sequence <220> <223> Control oligonucleotide <220> <221> beta-oxy-LNA nucloside <222> (1)..(4) <220> <221> phosphorothiate Internucleoside linkages <222> (1)..(16) <220> <221> beta-oxy-LNA nucloside <222> (14)..(16) <400> 823 gagaaggcac agacgg 16 <210> 824 <211> 15 <212> DNA <213> Artificial sequence <220> <223> Control oligonucleotide <220> <221> beta-oxy-LNA nucloside <222> (1)..(3) <220> <221> phosphorothiate Internucleoside linkages <222> (1)..(15) <220> <221> beta-oxy-LNA nucloside <222> (13)..(15) <400> 824 gcgaagtgca cacgg 15 <210> 825 <211> 16 <212> DNA <213> Artificial sequence <220> <223> Control oligonucleotide <220> <221> beta-oxy-LNA nucloside <222> (1)..(3) <220> <221> phosphorothiate Internucleoside linkages <222> (1)..(6) <220> <221> beta-oxy-LNA nucloside <222> (14)..(16) <400> 825 gagaaggcac agacgg 16 <210> 826 <211> 14 <212> DNA <213> Artificial sequence <220> <223> control oligonucleotide <220> <221> beta-oxy-LNA nucloside <222> (1)..(3) <220> <221> phosphorothiate Internucleoside linkages <222> (1)..(4) <220> <221> beta-oxy-LNA nucloside <222> (11)..(14) <400> 826 cgaaccactg aaca 14 <210> 827 <211> 15 <212> DNA <213> Artificial sequence <220> <223> Control oligonucleotide <220> <221> beta-oxy-LNA nucloside <222> (1)..(3) <220> <221> phosphorothiate Internucleoside linkages <222> (1)..(15) <220> <221> beta-oxy-LNA nucloside <222> (13)..(15) <400> 827 gaaccactga acaaa 15 <210> 828 <211> 15 <212> DNA <213> Artificial sequence <220> <223> Control oligonucleotide <220> <221> phosphorothiate Internucleoside linkages <222> (1)..(15) <220> <221> beta-oxy-LNA nucloside <222> (3)..(5) <220> <221> beta-oxy-LNA nucloside <222> (14)..(15) <400> 828 cagcgtaaag agagg 15 <210> 829 <211> 13 <212> DNA <213> Artificial sequence <220> <223> Control oligonucleotide <220> <221> beta-oxy-LNA nucloside <222> (1)..(2) <220> <221> phosphorothiate Internucleoside linkages <222> (1)..(13) <220> <221> beta-oxy-LNA nucloside <222> (11)..(13) <400> 829 gcgtaaagag agg 13 <210> 830 <211> 13 <212> DNA <213> Artificial sequence <220> <223> Control oligonucleotide <220> <221> beta-oxy-LNA nucloside <222> (1)..(3) <220> <221> phosphorothiate Internucleoside linkages <222> (1)..(13) <220> <221> beta-oxy-LNA nucloside <222> (12)..(13) <400> 830 cgaaccactg aac 13 <210> 831 <211> 16 <212> DNA <213> Artificial sequence <220> <223> Control oligonucleotide <220> <221> beta-oxy-LNA nucloside <222> (1)..(4) <220> <221> phosphorothiate Internucleoside linkages <222> (1)..(16) <220> <221> beta-oxy-LNA nucloside <222> (13)..(16) <400> 831 cgaaccactg aacaaa 16 <210> 832 <211> 16 <212> DNA <213> Artificial sequence <220> <223> Control oligonucleotide <220> <221> beta-oxy-LNA nucloside <222> (1)..(3) <220> <221> phosphorothiate Internucleoside linkages <222> (1)..(16) <220> <221> beta-oxy-LNA nucloside <222> (14)..(16) <400> 832 agcgaagtgc acacgg 16 <210> 833 <211> 15 <212> DNA <213> Artificial sequence <220> <223> Control oligonucleotide <220> <221> beta-oxy-LNA nucloside <222> (1)..(3) <220> <221> phosphorothiate Internucleoside linkages <222> (1)..(15) <220> <221> beta-oxy-LNA nucloside <222> (12)..(15) <400> 833 aggtgaagcg aagtg 15 <210> 834 <211> 15 <212> DNA <213> Artificial sequence <220> <223> Control oligonucleotide <220> <221> beta-oxy-LNA nucloside <222> (1)..(4) <220> <221> phosphorothiate Internucleoside linkages <222> (1)..(15) <220> <221> beta-oxy-LNA nucloside <222> (13)..(15) <400> 834 tagtaaactg agcca 15 <210> 835 <211> 15 <212> DNA <213> Artificial sequence <220> <223> Control oligonucleotide <220> <221> beta-oxy-LNA nucloside <222> (1)..(3) <220> <221> phosphorothiate Internucleoside linkages <222> (1)..(15) <220> <221> beta-oxy-LNA nucloside <222> (13)..(15) <400> 835 agaaggcaca gacgg 15 <210> 836 <211> 15 <212> DNA <213> Artificial sequence <220> <223> Control oligonucleotide <220> <221> beta-oxy-LNA nucloside <222> (1)..(3) <220> <221> phosphorothiate Internucleoside linkages <222> (1)..(15) <220> <221> beta-oxy-LNA nucloside <222> (13)..(15) <400> 836 ccgcagtatg gatcg 15 <210> 837 <211> 20 <212> DNA <213> Artificial sequence <220> <223> Primer <400> 837 atatgtggaa gccggaatct 20 <210> 838 <211> 22 <212> DNA <213> Artificial sequence <220> <223> primer <400> 838 tcccagaact ccctaatcag aa 22 <210> 839 <211> 20 <212> DNA <213> Artificial sequence <220> <223> primer <400> 839 atgacggtgg ctataccagg 20 <210> 840 <211> 22 <212> DNA <213> Artificial sequence <220> <223> Primer <400> 840 gggtcaatga tgagaacctt at 22 <210> 841 <211> 21 <212> DNA <213> Artificial sequence <220> <223> Primer <400> 841 gggcctcagc gtaatcctat t 21 <210> 842 <211> 26 <212> DNA <213> Artificial sequence <220> <223> Primer <400> 842 ttctgaagag aggtgatgac ttaaaa 26 <210> 843 <211> 20 <212> DNA <213> Artificial sequence <220> <223> Primer <400> 843 atccgaggca tgaatctcac 20 <210> 844 <211> 20 <212> DNA <213> Artificial sequence <220> <223> Primer <400> 844 caggccaaaa cccttgataa 20 <210> 845 <211> 20 <212> DNA <213> Artificial sequence <220> <223> Primer <400> 845 ttgctgagca tttttgcatc 20 <210> 846 <211> 16 <212> DNA <213> Artificial sequence <220> <223> negative control oligonucleotide <220> <221> beta-oxy-LNA nucleoside <222> (1)..(3) <220> <221> phosphorothiate Internucleoside linkages <222> (1)..(16) <220> <221> beta-oxy-LNA nucleoside <222> (14)..(16) <400> 846 ttgaataagt ggatgt 16

Claims (29)

  1. ◈청구항 1은(는) 설정등록료 납부시 포기되었습니다.◈
    10개 내지 30개의 뉴클레오티드 길이의 연속 뉴클레오티드 서열을 포함하는 안티센스 올리고뉴클레오티드로서, 서열 번호 585를 포함하거나 이로 구성되는, 안티센스 올리고뉴클레오티드.
  2. 삭제
  3. ◈청구항 3은(는) 설정등록료 납부시 포기되었습니다.◈
    제1항에 있어서,
    하나 이상의 2' 당 변형된 뉴클레오시드를 포함하는 안티센스 올리고뉴클레오티드.
  4. ◈청구항 4은(는) 설정등록료 납부시 포기되었습니다.◈
    제3항에 있어서,
    상기 하나 이상의 2' 당 변형된 뉴클레오시드가 2'-O-알킬-RNA, 2'-O-메틸-RNA, 2'-알콕시-RNA, 2'-O-메톡시에틸-RNA, 2'-아미노-DNA, 2'-플루오로-DNA, 아라비노 핵산(ANA), 2'-플루오로-ANA 및 잠금핵산(LNA) 뉴클레오시드로 이루어진 군에서 독립적으로 선택되는, 안티센스 올리고뉴클레오티드.
  5. ◈청구항 5은(는) 설정등록료 납부시 포기되었습니다.◈
    제3항에 있어서,
    상기 하나 이상의 2' 당변형된 뉴클레오시드가 LNA 뉴클레오시드인, 안티센스 올리고뉴클레오티드.
  6. ◈청구항 6은(는) 설정등록료 납부시 포기되었습니다.◈
    제1항에 있어서,
    상기 올리고뉴클레오티드가 하나 이상의 변형된 뉴클레오시드간 연결기를 포함하는, 안티센스 올리고뉴클레오티드.
  7. ◈청구항 7은(는) 설정등록료 납부시 포기되었습니다.◈
    제6항에 있어서,
    연속 뉴클레오티드 서열 내의 상기 뉴클레오시드간 연결기가 포스포로티오에이트 뉴클레오시드간 연결기인, 안티센스 올리고뉴클레오티드.
  8. ◈청구항 8은(는) 설정등록료 납부시 포기되었습니다.◈
    제1항에 있어서,
    상기 안티센스 올리고뉴클레오티드가 RNase H를 구성할 수 있는, 안티센스 올리고뉴클레오티드.
  9. ◈청구항 9은(는) 설정등록료 납부시 포기되었습니다.◈
    제8항에 있어서,
    상기 안티센스 올리고뉴클레오티드가 갭머(gapmer)인, 안티센스 올리고뉴클레오티드.
  10. ◈청구항 10은(는) 설정등록료 납부시 포기되었습니다.◈
    제1항에 있어서,
    상기 안티센스 올리고뉴클레오티드가 CMP 번호 585_1, 585_2, 585_3, 585_4, 585_5, 585_6, 585_7, 585_8, 585_9, 585_10, 585_11, 585_12, 585_13 및 585_14로 이루어진 군에서 선택되는, 안티센스 올리고뉴클레오티드.
  11. ◈청구항 11은(는) 설정등록료 납부시 포기되었습니다.◈
    제10항에 있어서,
    상기 안티센스 올리고뉴클레오티드가 CMP 번호 585_1인, 안티센스 올리고뉴클레오티드.
  12. 올리고뉴클레오티드 화합물 AAtTaTttatacacCATcAT(CMP 번호 585_1)인 안티센스 올리고뉴클레오티드로서, 여기서 대문자는 베타-D-옥시 LNA 뉴클레오시드를 나타내고, 소문자는 DNA 뉴클레오시드를 나타내고, 모든 LNA C가 5-메틸 시토신이고, 모든 뉴클레오시드간 연결기가 포스포로티오에이트 뉴클레오시드간 연결기인, 안티센스 올리고뉴클레오티드.
  13. 제1항, 제3항 내지 제12항 중 어느 한 항의 안티센스 올리고뉴클레오티드, 및 상기 안티센스 올리고뉴클레오티드에 공유 결합된 하나 이상의 접합체 모이어티(moiety)를 포함하는 접합체.
  14. 제1항, 제3항 내지 제12항 중 어느 한 항의 안티센스 올리고뉴클레오티드; 또는 상기 안티센스 올리고뉴클레오티드, 및 상기 안티센스 올리고뉴클레오티드에 공유 결합된 하나 이상의 접합체 모이어티를 포함하는 접합체; 및
    약학적으로 허용되는 희석제, 용매, 담체, 염 및 항원보강제(adjuvant) 중 하나 이상
    을 포함하는, 엔젤만 증후군(Angelman syndrome)의 치료 또는 예방에 사용하기 위한 약학 조성물.
  15. 제14항에 있어서,
    상기 약학적으로 허용되는 희석제가 포스페이트-완충된 염수(PBS)를 포함하는, 약학 조성물.
  16. 제14항에 있어서,
    상기 약학적으로 허용되는 염이 나트륨 염인, 약학 조성물.
  17. 제14항에 있어서,
    상기 약학적으로 허용되는 염이 칼륨 염인, 약학 조성물.
  18. 삭제
  19. 부계 UBE3A의 발현이 억제된 표적 세포에서 UBE3A 발현을 유도하는 시험관내 방법으로서,
    제1항, 제3항 내지 제12항 중 어느 한 항에 따른 안티센스 올리고뉴클레오티드; 또는
    상기 안티센스 올리고뉴클레오티드, 및 상기 안티센스 올리고뉴클레오티드에 공유 결합된 하나 이상의 접합체 모이어티를 포함하는 접합체; 또는
    상기 안티센스 올리고뉴클레오티드 또는 상기 접합체, 및 약학적으로 허용되는 희석제, 용매, 담체, 염 및 항원보강제 중 하나 이상을 포함하는 약학 조성물
    을 상기 세포에 유효량으로 투여하는 것을 포함하는, 방법.
  20. 제19항에 있어서,
    UBE3A의 발현이 대조군에 비해 40% 이상 증가하는, 방법.
  21. 제19항에 있어서,
    SNORD109B 하류의 SNHG14 전사체의 수준이 대조군에 비해 30% 이상 감소되는, 방법.
  22. 제19항에 있어서,
    상기 표적 세포가 뉴런 세포인, 방법.
  23. 제19항에 있어서,
    SNORD115의 발현이 대조군과 비해 유의미하게 영향을 받지 않는, 방법.
  24. 엔젤만 증후군의 치료 또는 예방에 사용하기 위한, 제1항, 제3항 내지 제12항 중 어느 한 항에 따른 안티센스 올리고뉴클레오티드; 또는 상기 안티센스 올리고뉴클레오티드 및 상기 안티센스 올리고뉴클레오티드에 공유 결합된 하나 이상의 접합체 모이어티를 포함하는 접합체; 또는 상기 안티센스 올리고뉴클레오티드 또는 상기 접합체 및 약학적으로 허용되는 희석제, 용매, 담체, 염 및 항원보강제 중 하나 이상을 포함하는 약학 조성물.
  25. 삭제
  26. 삭제
  27. 삭제
  28. 삭제
  29. 삭제
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Families Citing this family (22)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR101881596B1 (ko) 2008-12-02 2018-07-24 웨이브 라이프 사이언시스 재팬 인코포레이티드 인 원자 변형된 핵산의 합성 방법
SG177564A1 (en) 2009-07-06 2012-02-28 Ontorii Inc Novel nucleic acid prodrugs and methods of use thereof
WO2012039448A1 (ja) 2010-09-24 2012-03-29 株式会社キラルジェン 不斉補助基
EP2734208B1 (en) 2011-07-19 2017-03-01 Wave Life Sciences Ltd. Methods for the synthesis of functionalized nucleic acids
EP2872485B1 (en) 2012-07-13 2020-12-16 Wave Life Sciences Ltd. Asymmetric auxiliary group
KR102213609B1 (ko) 2012-07-13 2021-02-08 웨이브 라이프 사이언시스 리미티드 키랄 제어
JPWO2015108048A1 (ja) 2014-01-15 2017-03-23 株式会社新日本科学 抗腫瘍作用を有するキラル核酸アジュバンド及び抗腫瘍剤
WO2015108047A1 (ja) 2014-01-15 2015-07-23 株式会社新日本科学 免疫誘導活性を有するキラル核酸アジュバンド及び免疫誘導活性剤
AU2015207773B2 (en) 2014-01-16 2021-06-17 Wave Life Sciences Ltd. Chiral design
US10400243B2 (en) 2014-11-25 2019-09-03 Ionis Pharmaceuticals, Inc. Modulation of UBE3A-ATS expression
ES2852998T3 (es) 2015-11-12 2021-09-14 Hoffmann La Roche Oligonucleótidos para inducir la expresión de UBE3A paterno
EP3717646A4 (en) * 2017-12-01 2021-12-01 The Texas A&M University System ANTISENSE TREATMENT OF ANGELMAN'S SYNDROME
US11332733B2 (en) 2018-02-12 2022-05-17 lonis Pharmaceuticals, Inc. Modified compounds and uses thereof
CN108795935B (zh) * 2018-05-23 2022-06-21 中国农业科学院上海兽医研究所(中国动物卫生与流行病学中心上海分中心) 日本血吸虫SjELAV-like 1基因的siRNA及其应用
KR20210065125A (ko) * 2018-09-21 2021-06-03 유니버시티 오브 코네티컷 인간의 앤젤만 증후군에서 부계 ube3a 유전자 발현을 복원하기 위한 조성물 및 방법
CN113316722A (zh) * 2019-01-17 2021-08-27 豪夫迈·罗氏有限公司 E3泛素连接酶(ube3a)蛋白质靶标
AU2020253821A1 (en) * 2019-03-29 2021-10-28 Ionis Pharmaceuticals, Inc. Compounds and methods for modulating UBE3A-ATS
KR20210158859A (ko) * 2019-05-22 2021-12-31 더 유니버시티 오브 노쓰 캐롤라이나 엣 채플 힐 Ube3a 유전자 및 발현 카세트 및 이들의 용도
CN113874494A (zh) 2019-05-28 2021-12-31 豪夫迈·罗氏有限公司 产生单核细胞祖细胞的方法
JP2023529457A (ja) * 2020-06-09 2023-07-10 ロシュ イノベーション センター コペンハーゲン エーエス 治療用ポリヌクレオチドに使用するためのグアノシン類似体
US20240116278A1 (en) 2021-01-21 2024-04-11 Fujimori Kogyo Co., Ltd. Layered Film And Packaging Bag
WO2023217890A1 (en) 2022-05-10 2023-11-16 F. Hoffmann-La Roche Ag Antisense oligonucleotides targeting cfp-elk1 intergene region

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2014004572A2 (en) * 2012-06-25 2014-01-03 Isis Pharmaceuticals, Inc. Modulation of ube3a-ats expression

Family Cites Families (58)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4373084A (en) 1981-07-07 1983-02-08 E. I. Du Pont De Nemours And Company Sulfur-modified polypropylene ether glycols, a method for preparing them, and polyurethanes prepared therefrom
ATE239484T1 (de) 1991-10-24 2003-05-15 Isis Pharmaceuticals Inc Derivatisierte oligonukleotide mit verbessertem aufnahmevermögen
JP3756313B2 (ja) 1997-03-07 2006-03-15 武 今西 新規ビシクロヌクレオシド及びオリゴヌクレオチド類縁体
US6617162B2 (en) 2001-12-18 2003-09-09 Isis Pharmaceuticals, Inc. Antisense modulation of estrogen receptor alpha expression
IL135000A0 (en) 1997-09-12 2001-05-20 Exiqon As Bi- and tri-cyclic nucleoside, nucleotide and oligonucleotide analogues
US6238921B1 (en) 1998-03-26 2001-05-29 Isis Pharmaceuticals, Inc. Antisense oligonucleotide modulation of human mdm2 expression
WO2000040749A2 (en) * 1999-01-06 2000-07-13 Genenews Inc. Method for the detection of gene transcripts in blood and uses thereof
EP1152009B2 (en) 1999-02-12 2017-09-06 Daiichi Sankyo Company, Limited Novel nucleosides and oligonucleotide analogues
KR100782896B1 (ko) 1999-05-04 2007-12-06 엑시콘 에이/에스 Ｌ-리보-ｌｎａ 유사체
US6617442B1 (en) 1999-09-30 2003-09-09 Isis Pharmaceuticals, Inc. Human Rnase H1 and oligonucleotide compositions thereof
WO2001040794A1 (en) 1999-12-02 2001-06-07 Myriad Genetics, Inc. Protein-protein interactions
US6300132B1 (en) 1999-12-17 2001-10-09 Isis Pharmaceuticals, Inc. Antisense inhibition of telomeric repeat binding factor 2 expression
WO2001092582A1 (en) * 2000-06-01 2001-12-06 Genaissance Pharmaceuticals, Inc. Haplotypes of the ube3a gene
US20030087855A1 (en) 2001-09-13 2003-05-08 Isis Pharmaceuticals Inc. Antisense modulation of protein kinase R expression
CA2790034A1 (en) * 2001-06-21 2003-01-03 Isis Pharmaceuticals, Inc. Antisense modulation of superoxide dismutase 1, soluble expression
US20050124572A1 (en) * 2002-06-17 2005-06-09 Freier Susan M. Compositions and their uses directed to signal tranducers
WO2004016754A2 (en) 2002-08-14 2004-02-26 Pharmacia Corporation ANTISENSE MODULATION OF Nav1.3 EXPRESSION
JP2006500066A (ja) * 2002-09-25 2006-01-05 ファルマシア・コーポレーション ミクロソームのプロスタグランジンｅ２シンターゼ発現のアンチセンス調節
DK2284269T3 (en) 2002-11-18 2017-10-23 Roche Innovation Ct Copenhagen As Antisense design
KR20080109943A (ko) * 2003-08-29 2008-12-17 위스콘신 얼럼나이 리서어치 화운데이션 영장류 배아 줄기 세포 기원의 신경 줄기 세포, 운동 뉴런 및 도파민 뉴런의 시험관내 분화 방법
WO2007031091A2 (en) 2005-09-15 2007-03-22 Santaris Pharma A/S Rna antagonist compounds for the modulation of p21 ras expression
CN101437933B (zh) 2005-12-28 2013-11-06 斯克里普斯研究所 作为药物靶标的天然反义和非编码的rna转录物
KR20130042043A (ko) 2006-01-27 2013-04-25 아이시스 파마수티컬즈 인코포레이티드 6-변형된 바이시클릭 핵산 유사체
US20090326042A1 (en) 2006-05-05 2009-12-31 Isis Pharmaceuticals, Inc Compounds and methods for modulating expression of crp
US7666854B2 (en) 2006-05-11 2010-02-23 Isis Pharmaceuticals, Inc. Bis-modified bicyclic nucleic acid analogs
DK2066684T3 (da) 2006-05-11 2012-10-22 Isis Pharmaceuticals Inc 5´-Modificerede bicycliske nukleinsyreanaloge
US8580756B2 (en) 2007-03-22 2013-11-12 Santaris Pharma A/S Short oligomer antagonist compounds for the modulation of target mRNA
PE20090064A1 (es) 2007-03-26 2009-03-02 Novartis Ag Acido ribonucleico de doble cadena para inhibir la expresion del gen e6ap humano y composicion farmaceutica que lo comprende
WO2008150729A2 (en) 2007-05-30 2008-12-11 Isis Pharmaceuticals, Inc. N-substituted-aminomethylene bridged bicyclic nucleic acid analogs
WO2008154401A2 (en) 2007-06-08 2008-12-18 Isis Pharmaceuticals, Inc. Carbocyclic bicyclic nucleic acid analogs
WO2009006478A2 (en) 2007-07-05 2009-01-08 Isis Pharmaceuticals, Inc. 6-disubstituted bicyclic nucleic acid analogs
US8546556B2 (en) 2007-11-21 2013-10-01 Isis Pharmaceuticals, Inc Carbocyclic alpha-L-bicyclic nucleic acid analogs
WO2009090182A1 (en) 2008-01-14 2009-07-23 Santaris Pharma A/S C4'-substituted - dna nucleotide gapmer oligonucleotides
EP2285819B1 (en) 2008-04-04 2013-10-16 Isis Pharmaceuticals, Inc. Oligomeric compounds comprising neutrally linked terminal bicyclic nucleosides
WO2010036698A1 (en) 2008-09-24 2010-04-01 Isis Pharmaceuticals, Inc. Substituted alpha-l-bicyclic nucleosides
US8642334B2 (en) * 2009-02-17 2014-02-04 Memorial Sloan Kettering Cancer Center Methods of neural conversion of human embryonic stem cells
US9012421B2 (en) 2009-08-06 2015-04-21 Isis Pharmaceuticals, Inc. Bicyclic cyclohexose nucleic acid analogs
US10913929B2 (en) * 2009-10-13 2021-02-09 Stemcell Technologies Inc. Method of differentiating stem cells
CA2782373C (en) 2009-12-23 2019-03-26 Opko Curna, Llc Treatment of hepatocyte growth factor (hgf) related diseases by inhibition of natural antisense transcript to hgf
WO2011156202A1 (en) 2010-06-08 2011-12-15 Isis Pharmaceuticals, Inc. Substituted 2 '-amino and 2 '-thio-bicyclic nucleosides and oligomeric compounds prepared therefrom
CN103068982B (zh) 2010-07-14 2017-06-09 库尔纳公司 通过抑制盘状大同系物(dlg)的天然反义转录物而治疗dlg相关疾病
WO2012012467A2 (en) 2010-07-19 2012-01-26 Isis Pharmaceuticals, Inc. Modulation of nuclear-retained rna
WO2012022725A2 (en) * 2010-08-19 2012-02-23 F. Hoffmann-La Roche Ag Conversion of somatic cells to induced reprogrammed neural stem cells (irnscs)
US9714427B2 (en) 2010-11-11 2017-07-25 The University Of North Carolina At Chapel Hill Methods and compositions for unsilencing imprinted genes
WO2012068405A2 (en) 2010-11-17 2012-05-24 Isis Pharmaceuticals, Inc. Modulation of alpha synuclein expression
WO2012135621A2 (en) * 2011-03-30 2012-10-04 Cellular Dynamics International. Inc Priming of pluripotent stem cells for neural differentiation
JP2014514313A (ja) 2011-04-20 2014-06-19 ロシュ グリクアート アクチェンゲゼルシャフト 血液脳関門のｐＨ依存性通過のための方法及び構築物
US10023861B2 (en) 2011-08-29 2018-07-17 Ionis Pharmaceuticals, Inc. Oligomer-conjugate complexes and their use
US9751909B2 (en) 2011-09-07 2017-09-05 Marina Biotech, Inc. Synthesis and uses of nucleic acid compounds with conformationally restricted monomers
EP2850092B1 (en) 2012-04-09 2017-03-01 Ionis Pharmaceuticals, Inc. Tricyclic nucleic acid analogs
US20150291958A1 (en) 2012-11-15 2015-10-15 Roche Innovation Center Copenhagen A/S Anti apob antisense conjugate compounds
WO2014077693A1 (en) 2012-11-16 2014-05-22 Academisch Ziekenhuis Leiden H.O.D.N. Lumc Means and methods for reducing an effect of aging in a mammalian cell
EP3119881B1 (en) * 2014-03-21 2023-03-01 FUJIFILM Cellular Dynamics, Inc. Production of midbrain dopaminergic neurons and methods for the use thereof
ES2852998T3 (es) * 2015-11-12 2021-09-14 Hoffmann La Roche Oligonucleótidos para inducir la expresión de UBE3A paterno
CA3068304A1 (en) 2017-06-28 2019-01-03 University Of South Florida Modified ube3a gene for a gene therapy approach for angelman syndrome
EP3717646A4 (en) 2017-12-01 2021-12-01 The Texas A&M University System ANTISENSE TREATMENT OF ANGELMAN'S SYNDROME
CN111867638A (zh) 2018-01-26 2020-10-30 豪夫迈·罗氏有限公司 放射性标记的寡核苷酸及其制备方法
AU2020253821A1 (en) 2019-03-29 2021-10-28 Ionis Pharmaceuticals, Inc. Compounds and methods for modulating UBE3A-ATS

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2014004572A2 (en) * 2012-06-25 2014-01-03 Isis Pharmaceuticals, Inc. Modulation of ube3a-ats expression
US20150191723A1 (en) 2012-06-25 2015-07-09 Baylor College Of Medicine Modulation of ube3a-ats expression
JP2015529635A (ja) 2012-06-25 2015-10-08 アイシス ファーマシューティカルズ， インコーポレーテッド Ｕｂｅ３ａ−ａｔｓ発現の調節

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