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2 !&?OJ FH JA?JELA = JE E B = =J E CABBE?=?O BL=HE KI/16 AIE IIK?D=I AI FD=CEJEI C=IJHEJEI FAFJE?K?AH EJEI 6DEIHALEAM??A JH=JAI JDACA AH=JE FDOIE CE?= E F E?=JE B 6E =JA@ HC= I AOM H@I A =J E JHOFJ FD= AI FD=CEJEI C=IJHE?K?AH? EJEI FH IJ=C I EJHE? NE@A IA I HO AHLAI 1 64,761 A =J E 6EIIA?HAJA@FHE =HE O>OJDAFE A= C HAIF IAJ A LEH A J= =JE? K? AE 5 JDA = H?EH?=@E= I?E =J HI HACK =JE C?EH?=@E= HDOJD B K AH KI>E CE?= BK?JE I JD IA=HA? FH EIA@ KI L=I?K =H@EIA=IAI.EC 6=?JILE= / FH JAE? KF A@ A >H= AHA?AFJ HI IK?D=I 6 6 6! =JAIALAH= E JH=?A K =H AIIA CAHIIK?D=I?) 2?/ 2 = E AJDA FE A=?OJAI JDAA JAH A--?A IE /16 K? I=B H AH O A JAH?DH =BBE -?A I =HADECD OABBA?JELAE BIAH J E =HA= I = HI KH?A B 6 MDE?DEI JIJ HA@ >KJE A@E=JA OHA A=IA@KF JDA>E IO JDAIEIE J JDAANJH=?A K =HB =JE MDAHABH EJA=IE O?H IIAI?A A >H= AI BL=HE J I= EL= >E A?AHA>H IFE = B KE@ E KHE AAJ? = H?O? E?HACK =J H B 6CA AH=JE E FE A= C E C A LEH A J! =?JE CJDH KCD AKH= =?JEL=JE BJDA= JAHE H DOF JD= = KILE= JDA=N I BHAJE = C= C E?A IHK E CE JDA FJE? AHLAI H E CHAJE DOF JD= = E?JH=?J.EC 5 =HA? A?JA@MEJDFE A= C KCDF=H=LA JHE?K =H K? C E E?IO F=JDAJE? AKH I E AHL=JE CIKFAHE H?AHLE?= C= C E=MEJDF IJIO =FJE?IO F=JDAJE? AKH I IKFF OE CJDAFE A= C HAFE AFDHE A - HA A=IA@BH F IJC= C E E? IO F=JDAJE?BE>AHI=JFE A=?OJA A >H= A IJE K =JAIEJIα β =@HA?AFJ HI A=@E CJ =?JEL=JE B A >H= A> O =JA?O? =IA?) 2IOIJA HAIK JE CE JDAE?HA=IA BJDAE JH=?A K =H ALA B?) 2=IMA =I = FD IFD=JE@O E C O?AH JAE E =IA! AIIA CAHIIJE K =JAJDAANFHAIIE B)) )6 JDABEHIJH=JA E EJE CA O AE LAHJE CIAH J E J =?AJO IAH J E A AJDO JH= IBAH=IA01 6 E EJE C A O A JH= IB H E C =?AJO IAH J E J 6!.EC 6DAA O =JE? =?DE AHOB HJDA>E IO JDAIEI B 6E FE A=?OJAIBH 6HFJ 6M=IBEHIJ E@A JEBEA@>O)NA 6DA?EH?=@E= HDOJD MEJD= M ECDJ JE A ALA =H A@IKHCA=J@=H AIIFAHIEIJIE IJLAHJA>H=JAIEHHAIFA?JELA BMDAJDAH JDAEH HC= EI I=HA=?JELA@KHE CJDA@=O JE A H@KHE CJDA ECDJ $ 6DA

3 !&!.EC 5?DA =JE?HAFHAIA J=JE BJDAFE A= CH= AHCE?E AHL=JE ) 5?DA =JE? HAFHAIA J=JE B A =J E >E IO JDAIEIE FE A=?OJAI 2 =I = ALA I B 6=J@EBBAHA JJE A F E JI ECDJID ME C ECDJHEIA BJDAIA ALA I )CA HA =JA@B= E ECDJ A =J E HA A=IA, )@=FJA@BH 4AEJAH4 MEJD=KJD HFAH EIIE.EC JHOFH FD=?EH?K =JE CE A >OFE IB H A@JDH KCD JM H=JA E EJE CA O AF=JDM=OE J 6 MDE?DEI AJ=> E A@E JDA =E O MEJD>E AE J JDA/16

4 JOFE?= HDOJD E??D= CAIE F =I = 6 ALA IE DK = I=JL=HE KI=CAI=HA ID M.EC /16=FFA=HIJ >AJDA JANJH= FE A= I KH?A B?EH?K =JE C 6 MEJD K? I=??A JH=JE IAN?AA@E =I = ALA I>O "JE AI 6DEIL=IJ E /16??KHHE C@KHE CJDA@=O JE A =E J=E IJDA 6??A JH=JE E JDAFAHEFDAH= AIFA?E= B KA?A JA J B6HF MDE?DIAHLAI=I 6FHA?KHI H$ 0 MALAH K E AJDA E JDAFE A= C J JH JDAHA A=IA B 6BH /16EIHA =JA@J J= A MDE?DE JKH =FFA=HIJ AC=JELABAA@>=? E B KA?A B?EH?K =JE C 6$ )IID M HECE = O>O4=E D E LAJ O% 6 =E OE IAH J E HE?D--?A A=?JI> JD=I=F=H=?HE A A?K A /16 K? D H AHA A=IA@E J JDAF HJ= LAE 0KA JAHAJ= &? LE?E C O@A IJH=JA@JD=J H= =FF E?=JE B6HF C CE H=JI?=KIAI =H=FE@A AL=JE B?EH?K =JE C 6JD=JM=IDECDAHJD= JD=J >J=E A@=BJAHE F =@ E EIJH=JE BJDEI= E =?E@ 6DAE?HA A JE F =I = ALA B 6B ME C JDA6HF=FF E?=JE M=I=> EIDA@>O EC=JE BF HJ= LAE >KJHA =E A@ K =BBA?JA@>OFE A= A?J O CJD=J/16>OEJIA BEIJDA = HI KH?A B?EH?K =JE C 6=BJAH H= 6HF=FF E?=JE & 6DAIAIJK@EAI= I ID MA@JD=J/16 K? I=CA AH=JAI I >KJJDEI 6? JA JE JDA/16 E?HA=IAI = E EIJH=JE 5ALAH= JDAHIJK@EAIKIE C E K DEIJ?DA E K =II=OJA?D EGKAIL= E@=JA@>O02? BEH A@JDAFHAIA?A B 6E /16 K? JEBEA@--?A I=I JDA = HI KH?A B 6E /16 5E E =H O AII AHAJ=! MD IJK@EA@ JDA@EIJHE>KJE B 6E DK = DAF=J >E E=HO C=IJH E JAIJE = JH=?J? BEH A@ DECD??A JH=JE I B = E? K? I=MEJD =HCA = K JI AAN?HAJA@E J JDA>E A 6DAF =I = ALA B 6M=I= M=OI B >ADECDAHE F HJ= JD= E FAHEFDAH= O?EH?=@E= >KJAIFA?E= J= A 1JD=I>AA?? K@A@JD=J 6=?JI=I= A@E=J H BTE JAH HC=? K E?=JE >AJMAA ELAH! AJ=> EI B 6 EH?K =JE C 6EI AJ=> E A@ =E OE JDA ELAHJDH KCDJM = HIJAFI JDA? =IIE?= DO@H NO =JE F=JDM=O=JJDA$F IEJE >O?OJ?DH A2 " NOCA =IAIEI A O AI;2) = AIIAHANJA J ;2?=J= O E CJDAB H =JE B$ DO@H NO A =J E AI BKHJDAH? KC=JE MEJDAEJDAHIK FD=JA?=J= O A@>OIK FD JH= IBAH=IAJ B H $ IK FD A =J E HC K?KH E?=?E@?=J= O A@>O7,2 C K?KH IK JH= IBAH=IAJ B H $ DO@H NO A =J E C K?KH E@A" = = JAH =JA?=J=> E?F=JDM=O E? K@AI FA E C A? HA B 6@KHE C NE@=JE?=J= O A = E NOCA =IA H OA FAH NE@=IA 2 HAIK JE CE JDAB H =JE B K IJ=> AE JAH A@E=HO? F =?AJO B H O AJD NO O KH= E A!&"

5 !& ). MDE?D =O>AJH= IB H A@J HAIJ=> A =?AJO AJD NO O KH= E A) 6?= >A= I AJ=> E A@ A O =JE?= OE JDA?A I HANJH=?A K =H O >OBHAAH=@E?= JDAH NE@= JI$ ' 1JEI BE JAHAIJ JD=J= JE NE@= JE E B = =J HOFH FAHJEAI B 6=HA= I ID=HA@>OEJI O KH= E A@AHEL=JELAIIK?D=I). & ' 5 = = K JI B 6 =HAAN?HAJA@E J KHE AE K?D= CA@B H )I=DECD O EF FDE E?? F KCDJDA>E CE?= A >H= AIJ HA=?D= IJALAHO?A JH=?A K =H HC= IJ BJDA>E CE?= =?JE I B 6=HA A@E=JA@>O A >H= AHA?AFJ HI >KJI A JDAHI=HAHA?AFJ J! )?JEL=JE BFDOIE CE?= BK?JE IJDH KCDJDA=?JEL=JE B 6 6 6! JDAHHA?AFJ HIE? K@A I AAF FH FA IEJO I AAF M= AHDOJD?EH?=@E= HDOJD =JE E K AIOIJA NEBE?=JE BBHAAH=@E?= I FH JA?JE B/16 K? I= ELAH=C=E IJL=HE KI NE KI=CA JI? JH BJK HCH MJD > AB H =JE = O JDAHI?= E =JE IO JDAIEI B 6E /16 K? ELAH 5JK@EAIKIE C= 1 =>A A@ 6@AJA?JA@JDA@EIJHE>KJE BJEIIKA HA?AFJ HIB H 6E L=HE KIIFA?EAIE? K@E C E?A = I"! % CIEJAIB H 6D=LA>AA B = DOFAH> E?ID=FA C?KHLAIHALA= A@JD=JJDAH=@E > =I=JKH=> A K >AH CIEJAIF IIAIIE C=IE C AB= E O! 5 AMD=J CM=IB JDAAI FD=CKI MDE AJD=JE K A K K AK =IMA HA=?DA@JDADECDAIJ L= KA! 6??A JH=JE I A=IKHA@>O41)E JEIIKAD CA =JAI BE J=?J H=JIMAHA=> KJ JE AI MAHE JDACKJMDA? F=HA@J FE A= C 6HF=@ E EIJAHA@ H= OH=EIA@ 6>O=> JDAFE A= ELAH 6HFE?HA=IA@= I JDA?EH?K =JE C ALA I B 6 F=HJE?K =H OE JDAF HJ= LAE CAI B 6 ALA IE /16=BJAH 6HF=FF E?=JE MAHAK =BBA?JA@>OFHE HFE A= A?J O >KJCHA=J OHA@K?A@>O= F=HJE= EC=JE BJDAF HJ= LAE & 6DAIAIJK@EAIFH LE@A@IJH CALE@A?AJD=J /16 K? I= F=HJE?K =H OJD=J =? KIJAHK K DAF=J >E E=HOIOIJA ANDE>EJIDECD>E IO JDAJE?=?JELEJOB H 6 AIFA?E= O =BJAH =@E CMEJD6HF JDA 6FHA?KHI H KHANFAHE A J= IJK@EAI H=JIMEJD=FF E?=JE B 1 A =J E JH=?AH =@ E EIJAHA@E J JDA=HJAHE=?EH?K =JE BJDACKJ?A E=?=HJAHOE B=IJA@H=JI CIEJAIE /16 HALA= A@JD=JJDADECDAIJ ALA B =>A A@ JH=?AH A=IKHA@ E B ME CEJI=@ E EIJH=JE M=IB JDAE ELAH AIIE = E JAIJE = K? K A K K AK )BJAH! E JDA? JA J BJH=?AH =H A@ O@A? E A@AN?AFJ JDA A MDAHAJDADECDAIJH=@E =>A A@ 6 ALA IMAHAHA? H@A@ )J > JDAN= E =JE E JAHL= I JDADECDAIJ ALA I B =>A A@ 6MAHA@AJA?JA@E

6 !&$ I-MELATONIN bound (CPMx10 3 ) Esophagus Stomach After 15 min After 30 min Duodenum- -Jejunum Ileum Colon Liver Pancreas Portal vein blood plasma Hepatic vein blood plasma Bile.EC! C B 1 A =J E J L=HE KI/16JEIIKAI BJH=?AHH=@E =?JELEJO E F HJ= =I E KF JDAE JH==HJAHE= =FF E?=JE BJH=?AH F HJ=?EH?K =JE => KJ AIIE DAF=JE?LA 1 = JDAIAIJK@EAI JDAJH=?AH??A JH=JE E >E AAN?AA@A@JD=JE F HJ= 6DAIA HAIK JI=HA? HH > H=JELAMEJDFHALE KIIJK@EAI JDA 6HA?AFJ H@EIJHE>KJE E JDA/16 HECE = OHAF HJA@>O C! 6DA = H 6HA?AFJ HIE /16 =FFA=HJ >A 6 HA?AFJ HI 6 4=I@AJA?JA@>O A?K =H>E COJA?D EGKA E JDAC=IJHE? K? I=B ME BC=IJHE? K?AH=JE E = E = IJHA=JA@MEJD 6 H6HF 6DA/16 K? I= BJDA=@ E EIJAHA@ 6 JH=?AH@ AI J A?AII=HE OHAB A?JJDA=?JELEJO BL=HE KI HC= I BJDA@ECAIJELA IOIJA E JDA>E IO JDAIEI H AJ=> EI A 6DAHAB HA JDA E K HA=?JELA 6= I M=I A=IKHA@E H=JC=IJH E JAIJE = K? I= F=?HA=I=IMA =IE F HJ= JEIIKA D CA =JA =I A HAIFA?JELA O E JAIJIMEJD H= =@ E EIJH=JE B6HF C C 1 LADE? AI= E AJHA=JA@H=JI = /16 I= F IID MA@JDAFHAIA?A BE K HA=?JELA 6 6DADECDAIJ? JA J B 6E B=IJA@= E = IM=IHA? = A K = A= K? I= I AMD=J AIIE JDA ELAH JDA MAIJ ALA M=IB JDAAI FD=CA= H= JID M K? I= 1JEI BE JAHAIJJD=JH=JIMEJDHA LA@JDAFE A= C MA@IEC EBE?= J OI = AH

7 !&%??A JH=JE BF =I =E K HA=?JELA 6E LA M=I=JJDAI= AJE AIEC EBE?= J ODECDAHE F HJ= ALA. ME C6HF =@ E EIJH=JE >OA JAH= H KJA JDA/16 K? I= JDA ELAH=IMA =IF HJ= ID MA@IALAH= H@AHI B =C EJK@ADECDAH 6? JA JJD= JD=JE LADE? A JHA=JA@= E = I.EC " 2HALE KHFHA E E =HOHAIK JI? IK =HE A=IB MI /16 AIFA?E= =? KIJAHK EJ = > MA =HADECD OABBA?JELAE JDAIO JDAIEI B 6 A =J E BFE A= HECE EI HAIF IE> AB HJDA?JKH = HEIAE F =I = ALA BJDEID H A MDAHA=IJD=J HA? H@A@@KHE CJDA@=O JE A HECE =JAI =E OBH JDA/16 JDA ELAHEI?=F=> AJ =??K K =JA 6BH JDAF AJ=> E E CEJ EJI AJ=> EJAI=IMA =IJDAK?D= CA@ 6 A?K A=HAAN?HAJA@E J JDA>E A 6DA? F=HEI BFE A= 6CA AH=JE $IAA IJ FH LE@A ALE@A?AJD=JFE A= 6EIIA?HAJA@E?EH?=@E= B=IDE IAA.EC MDE A/16 AID ME J= A FH >=> AIO A=IABH JDA/16 A HECE =JE CBH JDAFE A= C AB=IDE MDE JDA/16>O--?A IFH >=> O=?JI =E OE F=H=?HE A K E = = AH 6DAHAEIALE@A?AJD=J K E AJDAFE A= C /16 F=HJE?K =H OJDA ELAH?= KFJ= A 6BH JDAF HJ=?EH?K =JE C JAH B=IJE C@A?HA=IAIJDA 6HA A=IABH JDAFE A= C Melatonin (pg/g tissue) Blood plasma Vehicle controls (C) Pinealectomized (Px) Px L-tryptophan Esophagus Stomach Duodenum- -Jejunum Ileum Colon Liver Pancreas.EC " ALA I BE K HA=?JELA 6E JDAF =I L=HE KI/16JEIIKAI F=?HA=IE LADE? A JHA=JA@B=IJA@? JH H=JI E B=IJA@FE A= A?J E A@2N= E = 2N = E = I=@ E EIJAHA@MEJD6HF=J=@ IA B C CCELA E JH=C=IJHE?= OE C

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

9 !&' EH HAIK JE CE AL=JE B0 >OJDA=?JE B5, 0 E? KC=JE MEJD CA AH=JAIDO@H NO H=@E?= IJD=J NE@E A?A K =H? IJEJKA JIIK?D=IA O FH JAE I A >H= A EFE@I AJAC KJ=JDE A EFE@FAH NE@=JE HAIK JIE JDA@A?HA=IA B A >H= A B KE@EJO E F=EHA@EH JH= IF A >H= AE JACHEJOMEJD II B?A K =H BK?JE I!" NE@=JELAIJHAII=FFA=HIJ KFHACK D=?AJDA=?JELEJO B E 5IOIJA =?? F= EA@>OJDA B =HCA= K JI B JD=J J CAJDAHMEJDIKFAH NE@A= E JDH KCD= HA=@O A JE A@ AJ=?=J= O A@0=>AH 9AEIIHA=?JE JDAFAH NO EJHEJAI CHA=J O? JHE>KJE CJ =CA!" 5JHAII= I?=KIAIF=HJE= E =?JEL=JE B?O? NOCA =IA : AH=JE BC=IJH FH JA?JELAFH IJ=C I2/JD=J??KH JDH KCD KJJDA E E C M J E DE>EJC=IJHE?=?E@ IA?HAJE E?HA=IA K? I= K =JA K?KI 0! IA?HAJE &!$ -NFHAIIE B : I@KA J HA@K?JE E =?JELEJO B : MDE?D H = OANAHJIJ E?E DE>EJ HO E B KA?A : ANFHAIIE I JDA2/? JA JE C=IJHE? K? I=HA =E I M!$ 6DA@A?HA=IAE K? I= 2/ AIFA?E= O2/1 ECDJHAIK JE DECDAH ALA B0 E IJHAIIA@C=IJHE? K? I=JD=JEI=?? F= EA@>OE?HA=IA@ 5,=?JELEJO 6DA?D= CAIE 5,=?JELEJO =O>A? IE@AHA@=I= =@=FJELA HAIF IAJ BIKFAH NE@A= E 5JHAII MF JA IE HA@K?AIJDAA A?JH JH= IF HJ?D=E MEJD IK>IAGKA J A= =CA BA A?JH IJ E?HA=IAJDAB KN B MDE?D =OHA A=IAEH H? FFAH A=@E CJ AN?AIIELACA AH=JE B 0?=KIE CFAH NE@=JE B EFE@?A K =H A >H= NE@=JELA@= =CAJ FH JAE JDAH =?H A?K AI 1JEI BE JAHAIJJD=JC=IJHE?FAH NE@=IA/2N = = H= JE NE@= JA O AE JDA C=IJHE? K? I= M=IB >AE =?JEL=JA@@KHE CIJHAIIFH >=> O>OAN?AIIELA O CA AH=JA@ 0?=KIE C NE@=JELA@= =CA IJ F =O= IEC EBE?= JH AE IJHAII & 6DAGKAIJE HA =E IMDAJDAH 6 CA AH=JA@E JDAC=IJHE? K? I=? K JAH=?JI JDAABBA?JI B >A@EI?KIIA@E =JAHF=HJ BJDEI=HJE? A A =J E E AI FD=CEJEI 6DAKFFAH/16 AIFA?E= OAI FD=CKI EIANF IA@J K AH KIEHHEJ= JIA JAHE C /16MEJDE CAIJA@ HHAB =? JA JIMEJD NE =CE H>E AI= JI 1 DK = I JDA C=IJH AI FD=CA= HAB KN@EIA=IA/-4,MEJD KJ -4, HMEJDAH IELA?D= CAIE AI FD=CA= K? I=EI?KHHA J OME@AIFHA=@@EI H@AH A=@E CAH KI? F E?=JE IIK?D=I?DH E?AI FD=CEJEI AI FD=CA= K?AH IJHE?JKHA =HHAJJ\I AI FD=CKI H=HHAJJ\I?=H?E = 1 JAHAIJE C O 2AHAEH=!&HAF HJA@ HA?A J OJD=J@EAJ=HOIKFF A A J=JE? J=E E C A =J E JHOFJ FD= MDE?DEI=IK>IJH=JAB H 6>E IO JDAIEIE F=JEA JIMEJD/-4, HAIK JA@E? F AJAHA EIIE B/-4,IO FJ IE = HEJO BJHA=JA@F=JEA JI 1JM=I

10 !'.EC 1 K B K HAI?A?A B A =J E E AI FD=CKI BH=JIMEJD KJ) HMEJD FHAJHA=J A JMEJDAN CA KI A =J E E FE I BJDACKJ,.H K>A E /)IAHEAIMEJD=KJD H\IFAH EIIE

11 !' ACROSCOPIC DAMAGE SCORE Series A M Series B Pla sma me la tonin (pg/ ml)l) 0 Veh Veh INDO L-NNA CAPS Veh INDO L-NNA CAPS Melatonin Acid-pepsin perfusion 0.EC $ =?H I? FE?AI FD=CA= K? I= AIE FD=CA= FAHBKIE FAFIE 5AHEAI)E? K@AIAI =CAI? =I = N AI FD=CA= K? I= 2/- CA AH=JE =IMA F =I = A =J E E K HA=?JELA??A JH=JE IE = AIJDAJE A@H=JIMEJD AI FD=CA= FAHBKIE MEJD=?E@ FAFIE E EIJH=JE BLADE? AI= E A AJ=D?E 1, C CE F ) C CE F?=FI=E?E )25 C CI? FHAJHA=J A J@=OI >AB HAE H=JI 5AHEAIE? K@AIJDAHAIK JIMEJDAI FD=CA= AIE =I = ALA I B A =J E K? I= CA AH=JE B2/- MEJDFHAJHA=J A JMEJD A =J E C CE F BH=JI MEJDAI FD=CA= FAHBKIE MEJD=?E@ FAFIE A AJD=?E ) H?=FI=E?E =IE IAHEAI))@=FJA@BH JKHA AJ= %?? K@A@JD=JJDAB H K =JE? J=E E C 6 HEJIFHA?KHI H 6HF FH JAI HACHAIIE B/-4,IO FJ IMEJD KJ= OIE@AABBA?JI 5JK@EAI B= E = IH=JIHALA= A@JDAFHAIA?A BE K BK HAI?A J 6E JDA AI FD=CKI F=HJE?K =H O=BJAH=@ E EIJH=JE BAN CA KI 6.EC ) 1 KHANFAHE A B/-4,E = AIJDAJE A@H=JIMEJD@=E O D FAHBKIE BAI FD=CKIMEJD=?E@ FAFIE MEJD HMEJD KJ>E AI KJE =H A@ FD=CA= AIE I E? K@E CFAHB H=JE BJDAAI FD=CA= M= E JDAKFFAHAI FD=CKI MAHA >IAHLA@ 9AB H =JE BJDAIA AIE IM=IFHALA JA@>OJDAFHAJHA=J A JMEJD A ANAHJIAI FD=C FH JA?JELA=?JELEJO!' 6DA A?D= EI BJDEI 6 AI FD=C A= FH JA?JE D=I J>AA BK O? =HEBEA@>KJEJ =O>A A@E=JA@ =J A=IJ E F=HJ >O : 5 IOIJA I=IMA =I>OJDA=?JEL=JE BIA I HO AHLAI>A?=KIAJDAFHAJHA=J A J B= E = AJD=?E IFA?EBE?

12 !' >? AH B : : ) = IFA?EBE?IKFFHAII H BJDA=?JELEJO B 5 H?=FI=E?E = AKH J NE JD=J?=KIAI=BK?JE = => =JE BJDA=BBAHA J IA I HO AHLAI IEC EBE?= J O=JJA K=JA@JDAFH JA?JELAABBA?JI B 6 AI FD=CA= =?H I? FE? AIE I.EC $.KHJDAH HA AJD=?E =JJDA@ IAKIA@ C CIKFFHAIIA@AI FD=CA= K? I=CA AH=JE B2/- >O=> KJ% MDE A ) C CHA@K?A@F =I = EJH=JA EJHEJA N ALA >O=> KJ$ JD AJD=?E )MAHA HAABBA?JELAE IKFFHAIIE CJDACA AH=JE B K? I= 2/- =I = N HAIFA?JELA O E 6 JHA=JA@= E = I=I? F=HA@ J LADE? A JHA=JA@H=JI 6DA?=FI=E?E FHAJHA=J A JM=IHA =JELA O AIIABBA?JELAE JDAHALAHI= BAI FD=C FH JA?JE 6= BIA I HO AHLAI>O?=FI=E?E IEC EBE?= J OHA@K?A@F =I = N IKCCAIJE CJD=J IA I HO AHLAI? JHE>KJAJ JDAAI FD=CA= FH JA?JE =E O>OIJE K =JE B CA AH=JE F IIE> OLE= HA A=IE CIA I HO AKH FAFJE@AIK?D?=?EJ E CA A HA =JA@FAFJE@A/42JD=JEI M J IJE K =JAJDA=?JELEJO B A=IA B FH JA?JE CJDA K? I= E E C B/16!' " )I KHFHALE KI OFHAIA JA@ IJK@EAIKIE CH=@E =>A A@ 6=C EIJ 1 A =J E HALA= A@JDA FHAIA?A B CIEJAIE AI FD=CA= K? I= M >AB HA JDA E K HA=?JELA 6M=I@AJA?JA@E JDA K? I= EJEI E A OJD=JJDA>A ABE?E= ABBA?JI BAN CA KI 6? C AJ JDA K? I= HA?AFJ HI 5E?AJDAFH JA?JELA=?JE B 6M=I=?? F= EA@>O E?HA=IA@ K? I= K=JA@>OFHAJHA=J A JMEJD : H E DE>EJ AJD=?E H ) HAIFA?JELA O FHAJHA=J A JMEJD?=FI=E?E E AKH J NE?@ IA C CJ E =?JEL=JAJDA IA I HO AHLAI!' MAFH F IAJD=J 6FH JA?JIAI FD=CA= K? I=>O E?HA=IE CJDEI K? I= MJDH KCDJDAA D=?A A J B2/ /42HA A=IAE JDA K? I= 6DEI JE EIIKFF HJA@>O CJD=JJDA E DE>EJE B : 2/IOIJA AJD=?E JD=JHALAHIA@>O 6 TAI FD=C FH JA?JELA]ABBA?J M=I=?? F= EA@>O=> KJ=%B= E AI FD=CA= K? I= ALA B2/- 5E E =H O JDAFHAJHA=J A J B= E = IMEJD )J IKFFHAII 5=?JELEJOM=IB MA@>O=> KJ=$B= E F =I = N ALA I CJD=J JDAB=E KHA BJDA K? A=IA B M=I JDA = HB=?J HE JDACHA=JAH@AJAHE H=JE BAI FD=CA= K? I= E JACHEJOMDA ANF IAJ?= EHHEJ= JIIK?D=I=?E@ FAFIE AFAHBKIE E KH= E = I 1JEI BE JAHAIJJD=JJDAIJH CAIJ@AJAHE H=JE BJDAAI FD=CA= K? I=FAHBKIA@MEJD =?E@F KIFAFIE I KJE M=I >IAHLA@B ME CE =?JEL=JE BIA I HO AHLAI MEJD?=FI=E?E J IKFFHAIIJDA K? I= HA A=IA B/42JD=JE JKH IJE K =JAIJDA >E IO A=IA@KAJ A D=?A 5ANFHAIIE EJEI HA=I => OJ =IIK AJD=J?=FI=E?E E H=JA@JDAAI FD=CKI JDH KCDJDAHA@K?JE E HA A=IAIAA.EC $ 6DEIEIIKFF HJA@>O CI JD=J?=FI=E?E E E J=?JH=JIHA@K?A@F =I = ALA I B HALAHIA@ =J A=IJE F=HJ >O=@@EJE B 6 AHL=JA@ H = FDOIE I JDAAI FD=C FH JA?JELA=?JELEJO B 6=C=E IJ /-4,? =JA@J JDAE DE>EJ HOABBA?J A C=IJHE?=?E@

13 !'! IA?HAJE IJE K =JE BC=IJHE HA A=IA% MDE?D ECDJ=JJA K=JAJDA C=IJH AI FD=CA= HAB KN>OIJE K =JE BJDA? JH=?JE A=?JELEJO BJDA MAH AI FD=CA= IFDE?JAH 6DEI =OE F OJD=J A =J E ANAHJIEJI>A ABE?E= C=IJH FD=C FH JA?JELA=?JE I= I LE= 6HA?AFJ HI?=JA@ C=IJHE C?A I D MALAH JDEIDOF JDAIEI=M=EJIBKHJDAHIJK@EAIJ E@A JEBOJDA AN=?J?A?=JE B 6 HA?AFJ HI 1JEI BE JAHAIJJD=JF=JEA H@AHIIK?D/-4, = K?AHID MHA@K?A@F =I = ALA I B 6 MDE?DIKCCAIJIJD=JJDA@ABE?EA?O AANAHJI@AJHE A J= ABBA?JI JDAKFFAH/16 K? I=!' " 6DEIEIE =CHAA A JMEJDFHALE KI IJK@EAIE DK = IMEJD@EAJ=HOIKFF A A J=JE? J=E E C MDE?D HAIK JA@E? F AJAHA? LAHO B/-4,IO FJ I=BJAHIK?DJHA=J A J!& A =J E E =?KJAC=IJHE?@= =CA. ME CJDA@EI? LAHO B 6E JDAFE A= C AH AHAJ= "! = IJ D= B?A JKHO=C K AH KIIJK@EAIE@A JEBEA@JDA?= E B AE L=HE KIANJH=FE A= JEIIKAI E? K@E C/16 F=HJE?K =H OJDAIJ =?D I = > MA &! "" "% 6DAE@A JEBE?=JE B =HCAH= K JI B 6 E /16 K? I= HALA= A@F=HJE?K =H O@KHE CJDA@=OJE A>O0KAJDAHAJ= AII AHAJ=! M=IE EJE= OE JAHFHAJA@JD=JJDA/16=?JI=I=I HJ B=]IE ^ B HJDA?EH?K =JE A HECE =JE CBH FE A= 0 MALAH BKHJDAHIJK@EAI E? K@E CJDEIF=FAH D=LAFH LE@A@= ALE@A?AB JIO JDAIEI B 6E HEJIIA?HAJE E J JDAFAHEFDAH=?EH?K =JE $ 1JM=I?=?K =JA@JD=JJDA@ECAIJELAIOIJA? J=E I=> KJ"JE AI =HCAH= K JI B 6JD= FE A= C JDAIE A@E /16 K? I=>O--?A I IAA.EC CJDA@=OJE A AIFA?E= OE HAIF IAJ J= A$ 6DEID=I>AA? BEH A@E KHIJK@O ID ME CJD=JE JH=C=IJHE?=FF E?=JE B6HFCHA=J OA AL=JAIJDA? JA J B 6E JDA/16 K? ELAH.EC " )I 1 =>A A@ 6=FF EA@E JH==HJAHE= O =FFA=HA@= IJE A@E=JA OE JDA E JDA>E A.EC EJIE F O ELAHKFJ= AI?EH?K =JE C 6 F=HJE?K =H OE F HJ= LAE AN?HAJAIEJE J JDAJDA>E A 6DKI /16=FFA=HIJ >A= = JAH =JELAANJH=FE A= I KH?A B 6MDE?DEIFH >=> I B/16BH JHOFH FD= HECE =JE CBH JDAE CAIJA@FH JAE A=IA@E =HCAGK= JEJEAIJ JDAI = > 6DA?= E =JE B 6E /16>OE K?OJ?DA EIJHO>OK>A E AJ= H=EIAI= E F HJ= JGKAIJE??AH E CJDAFDOIE CE?= IEC EBE?=?A BJDEI A IO JDAIE A@E F=HJE?K =H O =HCA= K JIE JDAC=IJHE? K? I="',KA J DECD EF FDE E?FH FAHJEAI --?A I ECDJ LAE =OAHI B K? I=J =BBA?J K? I= E?H?EH?K =JE IK> K? I= J =?J KI?K =HEI ANKI OA JAHE?KI "' MDAHA KIE C E K?DA EIJHO IK>IJ= JE= = K JI B 6MAHAE@A JEBEA@ $

14 !'" ) Wistar rat MEAN LESION NUMBER Lumina l NO (µm) Pla sma mela tonin (pg/ ml) 0 Intact Veh MELATONIN (mg/kg i.g.) Intact Veh L-TRYPTOPHAN (mg/kg i.g.) 0.EC B=?KJAC=IJHE? AIE EGKAKIA@E IAI B A =J E IAI B JHOFH FD= A= C=IJHE? AIE 945=IMA =I K E = HA A=IA B =I = A =J E??A JH=JE IE H=JI=@=FJA@ BH JKHA AJ= $ IE@AHE CJDADECDABBA?JELA JA?O B = H AJ=> EJAIE I?=LA CE C B4 5 4 JDAH NE@= JI=IMA =IJDAEH=>E EJO J IJE K =JA JE NE@=JELAA O AI MAIJK@EA@JDA=?JELEJO BI A B JDAIAA O AIE KHANFAHE A I B NE@=JELAIJHAIIK?AH=JE I B=?KJAC=IJHE? AIE IE H=JIE? K@A@JDA? >E =JE BHAIJH=E AHIE > JD=?JE CIO AHCEIJE?= OJ AIE I JDKI E E? E CJD IAKIK= O@ALA FA@E DK = C=IJHE? K? I= 6DEI JA?D EGKA=FF EA@>O KHCH KFFHALE KI OM=IB >ADECD OABBA?JELAE JDA BC=IJHE? K? I= E KHO=?? F= EA@>O@A?HA=IA@ K? I= B M F IIE> E A B E?H?EH?K =JE! 1 JDAFHAIA JIJK@O MA A=IKHA@F =I = ALA I BE K HA=?JELA 6=BJAHE C =@ E EIJH=JE B CH=@A@@ IAI A C C H6HF C C.EC % 1JM=I B JD IA J O=JJA K=JA@C=IJHE? AIE I? HA 6DEIABBA?JM=I=?? F= EA@E > JD?=IAI>O=F=H= A HEIA BF =I = ALA I B E?HA=IAE F =I = ALA I B K? I= M 6DKI JDA C=IJH FH JA?JELAABBA?JI B H6HF? JDA E?HA=IA BF =I K? I= ALA I B 6JD=JFH >=> OIJE K =JA@JDA B >OJDA K? K? I= E?H?EH?K =JE > JD? JHE>KJE CJ JDAHA@K?JE B945 K? =CA

15 !' MEAN LESION NUMBER GBF (% of control) 0 Veh (mg/kg) MT (mg/kg) L-TRP Veh Veh MT L-TRP MT L-TRP CAPSAICIN 0 CGRP (10 µg/kg s.c.).ec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

16 !'$ HAIJH=E JIJHAII945 HAIK JE CE K JEF AC=IJHE?AH IE IE = JAIJA@H=JI JDAHA M=I=IEC EBE?= JB= E C? JA J A BJDA = B EFE@FAH NE@=JE E C=IJHE? K? I=E LADE? A JHA=JA@H=JI.EC ' 6DAE JH=C=IJHE?=@ E EIJH=JE B 6 C C H 6HF C C JD=JHA =H => OFHALA JA@JDAIJHAII =CA = IJ? F AJA OHALAHIA@JDAB= =IHA@K?A@ EFE@ FAH NE@=JE J JDAL= KAIHA? H@A@E LADE? A JHA=JA@= E = IMEJD KJIK>IAGKA J ANF IKHAJ 945.KHJDAHIJK@EAI=HA AA@A@J? =HEBOMDAJDAHJDA=> LA A JE A@>E?DA E?=?D= CAIE = JE NE@=JELAA O EFE@FAH NE@=JE??KHE = E = IMEJDHA LA@FE A= E EIJH=JE 1 IK =HO JDAIAHAIK JI? CIJD=J E JH=C=IJHE? 6EIDECD OABBA?JELAC=IJH FH JA?J H=C=E IJ NE@=JELAIJHAII AIE I.KHJDAH HA JDAE JH=C=IJHE?=@ E EIJH=JE B6HF MDE?DHAIK JI E =H=FE@? LAHIE BJDEI= E =?E@E J 6 EIDECD OABBA?JELAE FHALA JE BC=IJHE?IJHAII =CA>O= E?HA=IAE C=IJHE? K? I=?EH?K =JE F IIE> OHAIK JE CBH I?=LA CA BBHAAH=@E?= I IJE K =JE B= JE NE@=JELA A O AIE JDAC=IJHE? K? E EFE@FAH NE@=JE.KHJDAHIJK@EAI =HA AA@A@J A K?E@=JAMDAJDAH H= O=FF EA@ 6 H6HF=?JI =E OLE= F=H=?HE A A = AHE =BB H@E CDECD OABBA?JELAC=IJH FH JA?JE KHHAIK JIHAC=H@E CC=IJH FH JA?JE B 6=C=E IJ=?KJAC=IJHE? AIE I =?? H@MEJD JDAHHAF HJIID ME A HEJI ,2 2 0 SOD (U/ g) ,8 0,4 GSH (µmol/ g) MDA 4-HNE (nmol/ g) 0 Vehicle Vehicle MT (10 mg/kg) L-TRP (200 mg/kg) 0 WRS-Stress.EC ' /=IJHE? K? I= K? I=? JA JI NE@=JE = "0 -E H=JIIK> A?JA@J! D AI= E A HMEJD A =J E C CE C H6FH C CE C =IE ANFAHE A JIID M.EC %

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

18 !'& (A) COX-2 ß-actin 3 (B) mrna COX-2/ / -actin mrna ratio IntactVeh IntactAAulcer AA-ulcer IntactAA-ulcerMT ulcermt IntactAAulcerTrp ulcertrp IntactVeh IntactAAulcer ulcer IntactAAulcerMT ulcermt IntactAAulcerTrp ulcertrp Day 0 After ulcer induction Day 8 MT TRP.EC /=IJHE? K? I= 4 )ANFHAIIE B H : =?JE E E J=?JH=JI LADE? H=JIMEJD=?AJE? 6DACA AANFHAIIE B H : M=I A=IKHA@E A=?D= E = E JDA K? I==JJDA FF IEJAJ K?AH=HA=E H=JIMEJDJHA=J A JMEJD 6 H6HF) )IJAHEI EBE?= JE?HA=IA? F=HA@J JDA L= KAHA? H@A@E JDAE J=?J K? I=HA JABH JDAK?AH=JA@ K? I= H EBE?= J E?HA=IA=I? F=HA@J JDAL= KAIHA? E? C K? I= =HA=K?AH=JA@ H K?AH=JA@ K? I= )IJAHEI EBE?= JE?HA=IAI=I? F=HA@J K?AH=JA@ K? I=MEJD KJ HMEJD 6 H6HF=@ E EIJH=JE B C=IJHE?K?AHIKIE CIAH I= =FF E?=JE B6HF H 6=@ E EIJH=JE DA= E C BJDAIAK?AHI=I? F=HA@MEJDJDADA= E CB ME C=@ E EIJH=JE BLADE? A )IJAHEI EBE?= J@A?HA=IA>A MJDAE EJE= L= KAHA? H@A@=J@=O!=BJAHE EJE=JE BK?AHI H EBE?= J@A?HA=IA>A MJDAL= KA >J=E A@MEJDLADE? AJHA=J A J =??A AH=JE BJDAK?AHDA= E C )?? H@E CJ >IAHL=JE BK>A E AJ= $' FECIMEJDIF J= A KIC=IJHE?K?AHIANDE>EJIEC EBE?= J O MAH??A JH=JE I B 6E =I =,EAJ=HOIKFF A A J=JE MEJDI IA B 6 C C BAA@IEC EBE?= J OHA@K?A@JDAE?E@A?A B C=IJHE?K?AH )? =HIA OCH HAE FECI JDEID=I>AA ANF =E A@>OJDAE?HA=IAE K? I=? JA J BC=IJH FH JA?JELA 6 F=@DO=OAJ= % %!ID MA@E ANFAHE A J= IJD=J A =J E =IC=IJH FH JA?JELAIK>IJ=?A =O>AKIABK =I=? JHA=J A JMEJD

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ntact gastric mucosa Site of inflammation at ulcer bed Arachidonic acid Enzyme induction COX-1 constitutive Enzyme activity (-) () NSAID Enzyme induction COX-2 inducible Enzyme activity (-) () () MT or TRP Physiological prostaglandin (e. g. gastric protection) Pathological prostaglandins (e. g. inflammation) Acceleration of ulcer healing.ec 5?DA =JE?FHAIA J=JE B : : ANFHAIIE E J=?JC=IJHE? K? H=JIJHA=JA@MEJD 5)1,MEJD 6 H6HFJDAH=FO

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