Harm Reduction Associated with Inhalation and Oral Administration of Cannabis And
+DUP5HGXFWLRQ$VVRFLDWHG ZLWK,QKDODWLRQDQG2UDO$GPLQLVWUDWLRQ RI&DQQDELVDQG7+&
)UDQMR*URWHQKHUPHQ
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Ó E\ 7KH +DZRUWK 3UHVV ,QF $OO ULJKWV UHVHUYHG@
)UDQMR *URWHQKHUPHQ LV DIILOLDWHG ZLWK QRYD,QVWLWXW *ROGHQEHUJVWUDH ' +UWK*HUPDQ\ (PDLOIUDQMRJURWHQKHUPHQ#QRYDLQVWLWXWGH >+DZRUWK FRLQGH[LQJ HQWU\ QRWH@ ³+DUP 5HGXFWLRQ $VVRFLDWHG ZLWK ,QKDODWLRQ DQG 2UDO $GPLQLVWUDWLRQ RI &DQQDELV DQG 7+&´ *URWHQKHUPHQ )UDQMR &RSXEOLVKHG VLPXOWDQHRXVO\LQ-RXUQDO RI &DQQDELV 7KHUD SHXWLFV 7KH +DZRUWK ,QWHJUDWLYH +HDOLQJ 3UHVV DQ LPSULQW RI 7KH +DZRUWK 3UHVV ,QF 9RO 1R SS DQG &DQQDELV 7KHUDSHXWLFV LQ +,9$,'6 HG (WKDQ 5XVVR 7KH +DZRUWK ,QWHJUDWLYH +HDOLQJ 3UHVV DQ LPSULQW RI 7KH +DZRUWK 3UHVV ,QF SS 6LQJOH RU PXOWLSOH FRSLHV RI WKLV DUWLFOH DUH DYDLODEOH IRU D IHH IURP 7KH +DZRUWK 'RFXPHQW 'HOLYHU\ 6HUYLFH > DP SP (67 (PDLODGGUHVVJHWLQIR#KDZRUWKSUHVVLQFFRP@ E\7KH +DZRUWK 3UHVV,QF$OOULJKWVUHVHUYHG &$11$%,67+(5$3(87,&6,1+,9$,'6
.(<:25'6 &DQQDELV PDULMXDQD 7+& FDQQDELQRLGV VPRNLQJ LQ KDODWLRQ RUDO XVH UHFWDO XVH VXEOLQJXDO XVH WUDQVGHUPDO XVH WKHUDSHXWLF XVH VLGH HIIHFWV KHDOWK ULVN KDUP UHGXFWLRQ FDQFHU VSRQWDQHRXV SQHXPR WKRUD[ GRVLQJRYHUGRVHRSLXPRSLDWHVSKDUPDFRNLQHWLFV
,1752'8&7,21
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Ϫ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
3+$50$&2.,1(7,&6
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
TABLE 1. Pharmacokinetic comparison of THC application to humans via in- travenous, respiratory and oral routes. (Agurell et al. 1986, Azorlosa et al. 1992, Frytak et al. 1984, Wall et al. 1983, Ohlsson et al. 1980, Perez-Reyes et al. 1981, Perez-Reyes et al. 1973)
Parameter Intravenous Inhaled Oral (lipophilic vehicle) Absorption 100% 10-30 (up to 50)% > 95% Systemic bioavailability 100% 10-30 (up to 50)% 10-20% Psychotropic threshold per kg 0.02 mg/kg 0.06-0.1 mg/kg 0.2-0.3 mg/kg body weight Psychotropic threshold per 1 mg 3-6 mg ca. 10-20 mg individual Maximum plasma concentration 30-50 ng/ml 30-50 ng/ml 3-5 ng/ml at the psychotropic threshold Dose producing marked 2-4 mg 10-20 (up to 50) mg 30-40 (up to 90) mg intoxication* Onset of action within seconds within seconds 30-60 (up to 120) min Duration of action** 2-3 (up to 4) h 2-3 (up to 4) h 5-8 (up to 12) h * Doses producing a marked intoxication vary according to duration of therapy. Longer use may result in the development of tolerance, and higher doses are needed to achieve the similar effects. ** Duration of action varies according to examined effect and especially with oral use according to dose.
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
5,6.62)602.,1* 0RUH WKDQ FRPEXVWLRQ SURGXFWV KDYH EHHQ IRXQG LQ PDULMXDQD VPRNH 6SDUDFLQR HW DO DQG PDQ\ DUH NQRZQ WR EH WR[LF WR WLVVXHV RI WKH UHVSL )UDQMR*URWHQKHUPHQ
UDWRU\ DQG XSSHU LQWHVWLQDO WUDFW $VLGH IURP WKH QLFRWLQH FRQWHQW FDQQDELV VPRNH LV TXDOLWDWLYHO\ VLPLODU WR WKDW RI WREDFFR 7DVKNLQ %HQ]R> @DQ WKUDFHQH DQG EHQ]R> @S\UHQH WZR KLJKO\ SURFDUFLQRJHQLF SRO\F\FOLF DUR PDWLF K\GURFDUERQV 3$+V DUH SUHVHQW LQ KLJKHU FRQFHQWUDWLRQV LQ WKH WDU IURP FDQQDELV DV FRPSDUHG WR WREDFFR /HH HW DO 7KH GHSRVLWLRQ RI 3$+V LV DPSOLILHG DSSUR[LPDWHO\ WLPHV E\ D KLJKHU WDU \LHOG RI XQILOWHUHG PDULMXDQD FLJDUHWWHV FRPSDUHG WR ILOWHUWLSSHG WREDFFR FLJDUHWWHV DQG D ORQJHU EUHDWKKROGLQJ WLPH ZLWK PDULMXDQD :X HW DO $ IROG ORQJHU EUHDWK KROGLQJ UHVXOWV LQ D JUHDWHU GHSRVLWLRQ RI WDU LQ WKH UHVSLUDWRU\ WUDFW :X HW DO :KHWKHU WKLV KLJKHU WDU \LHOG IURP FDQQDELV VPRNH OHDGV WR D IRXUIROG VWURQ JHU GDPDJH RI WKH PXFRVD FRPSDUHG WR VPRNLQJ WKH VDPH DPRXQW RI WREDFFR LV XQFOHDU $ IRXUIROG LQFUHDVH PD\ EH UHJDUGHG DV WKH ZRUVWFDVH VFHQDULR ZKHUHE\ VPRNLQJ KDOI D FDQQDELV FLJDUHWWH DERXW JUDPV RI FDQQDELV ZRXOG GDPDJH WKH PXFRVD WR D VLPLODU GHJUHH DV WZR WREDFFR FLJDUHWWHV VHH )LJXUH +LVWRSDWKRORJLFDO DOWHUDWLRQV RI WKH DLUZD\V DVVRFLDWHG ZLWK VPRN LQJ PD\ OHDG WR FKURQLF EURQFKLWLV DQG K\SRWKHWLFDOO\ HYHQWXDOO\ WR FKURQLF
FIGURE 1. Assumed risk associated with smoking herbal cannabis vs. THC content (as % of the dried plant material) corresponding to that caused by to- bacco cigarettes. The worst-case scenario is assumed, that smoking a certain amount of cannabis increases the risk of respiratory cancer and other damage 4 times higher than smoking the same amount of tobacco (see text). The risk of 0.2 grams of cannabis corresponded to 1 tobacco cigarette. Depending on THC content 0.2 grams of cannabis contain 4 mg (2% THC), 10 mg (5% THC), 20 mg (10% THC) or 40 mg THC (20% THC). About 4 puffs are needed to smoke 0.2 grams of cannabis (see Table 2).
Assumed damage from smoking 5, 10, 20 or 40 mg of THC in cannabis versus THC content 10 9 5mgTHC 8 7 10 mg THC 6 5 20 mg THC 4 40 mg THC 3
Assumed damage 2
(tobacco euqivalent) 1 0 2 4 6 8101214161820 THC content (%) &$11$%,67+(5$3(87,&6,1+,9$,'6
REVWUXFWLYH SXOPRQDU\ GLVHDVH &23' (SLGHPLRORJLFDO DQG H[SHULPHQWDO GDWD ZLWK UHJDUG WR &23' DUH FRQIOLFWLQJ KRZHYHU 3URJUHVVLYH DLUZD\V QDU URZLQJ LQ &23' FDQ EH GHWHFWHG E\ DQ DFFHOHUDWHG GHFOLQH LQ WKH IRUFHG H[SL UDWRU\ YROXPH LQ RQH VHFRQG )(9 DQG E\ D GHFUHDVHG UDWLR RI )(9 WR IRUFHG YLWDO FDSDFLW\ )9& ,Q D VWXG\ E\ %ORRP HW DO PDULMXDQD VPRNHUV VKRZHG VLJQLILFDQW ORZHU YDOXHV IRU WKH )(9 )9& UDWLR WKDQ QRQ VPRNHUV DQG WREDFFR VPRNHUV 7KH SUHYDOHQFH RI UHVSLUDWRU\ V\PSWRPV ZDV LQFUHDVHG $ \U IROORZXS VWXG\ ZLWK VXEMHFWV GHPRQVWUDWHG D VLJQLIL FDQW UHGXFWLRQ LQ )(9 DQG )(9)9& LQ SUHYLRXV PDULMXDQD XVHUV EXW QRW LQ FXUUHQWXVHUV 6KHUULOOHWDO ,Q FRQWUDVW WR WKHVH ILQGLQJV D VWXG\ E\ 7DVKNLQ HW DO FRPSDULQJ PDUL MXDQD VPRNHUV WREDFFR VPRNHUV VPRNHUV RI ERWK WREDFFR DQG PDULMXDQD DQG QRQVPRNHUV GLG QRW UHYHDO DQ\ DVVRFLDWLRQ EHWZHHQ KHDY\ XVH RI PDULMXDQD IRU PRUH WKDQ \HDUV DQG UHVXOWLQJ GHFUHPHQWV LQ SXOPRQDU\ IXQFWLRQ 1RQH RI WKH YDOXHV RI WKH DSSOLHG VHQVLWLYH PHDVXUHV ZDV GLIIHUHQW IURP WKH DYHUDJH YDOXHV REVHUYHG LQ QRQVPRNHUV ,Q D VHFRQG VWXG\ 7DVKNLQ HW DO RQFH PRUH IDLOHG WR ILQG DQ\ DVVRFLDWLRQ EHWZHHQ PDULMXDQD XVH DQG OXQJ IXQFWLRQ DEQRU PDOLW\ )(9 ZDV PHDVXUHG LQ KHDY\ KDELWXDO VPRNHUV RI PDULMXDQD DORQH VPRNHUV RI PDULMXDQD SOXV WREDFFR UHJXODU VPRNHUV RI WREDFFR DORQH DQG QRQVPRNHUV RI HLWKHU VXEVWDQFH DQG LQ VXEMHFWV RQ XS WR VL[ DGGL WLRQDO RFFDVLRQV RYHU D SHULRG RI \HDUV ,Q QHLWKHU PHQ QRU ZRPHQ ZDV PDUL MXDQD VPRNLQJ DVVRFLDWHG ZLWK JUHDWHU GHFOLQHV LQ )(9 WKDQ QRQVPRNLQJ QRU ZDV DQ DGGLWLYH HIIHFW RI PDULMXDQD DQG WREDFFR QRWHG QRU D VLJQLILFDQW UHODWLRQ VKLS IRXQG EHWZHHQ WKH QXPEHU RI PDULMXDQD FLJDUHWWHV VPRNHG SHU GD\ DQG WKH UDWH RI GHFOLQH LQ )(9 ,Q FRPSDULVRQ WREDFFR VPRNLQJ ZDV DVVRFLDWHG ZLWK JUHDWHU DQQXDO UDWHV RI GHFOLQH LQ OXQJ IXQFWLRQ WKDQ QRQVPRNLQJ 7KH DXWKRUV FRQFOXGHG WKDW ³WKHVH ILQGLQJV GR QRW VXSSRUW DQ DVVRFLDWLRQ EHWZHHQ UHJXODU PDULMXDQD VPRNLQJ DQG FKURQLF &23' EXW GR QRW H[FOXGH WKH SRVVLELOLW\ RI RWKHU DGYHUVH UHVSLUDWRU\ HIIHFWV´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
+$505('8&7,21:,7+,1+$/$7,21
7KHPDMRUVWUDWHJLHVWRUHGXFHWKHULVNVRIVPRNLQJDUH
•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ϫ PJ DQG ϫ PJ GURQDELQRO $EUDPV HW DO XVHG VPRNHG FDQQD ELV 7+& DQG RUDO GURQDELQRO ϫ PJ 'XH WR WKH GHYHORS PHQW RI VRPH WROHUDQFH GRVHV DUH RIWHQ LQFUHDVHG XS WR PJ ZLWK ORQJ GXUDWLRQ RI WKHUDS\ SHUVRQDO FRPPXQLFDWLRQV IURP VHYHUDO SK\VLFLDQV HTXLYDOHQW WR RQH TXDUWHU RI D PDULMXDQD FLJDUHWWH FRQWDLQLQJ PJ RI FDQQDELVRI7+& • 7KH XVH RI SXUH FDQQDELV 6RPHWLPHV FDQQDELV LV VPRNHG WRJHWKHU ZLWK WREDFFR RU RWKHU GULHG KHUEV 7KLV SURFHGXUH VKRXOG EH DYRLGHG WR PLQL PL]HWKHLQKDODWLRQRIVPRNHIURPEXUQWSODQWPDWHULDO &$11$%,67+(5$3(87,&6,1+,9$,'6
• 7KH XVH RI SLSHV 3LSHV DUH VXSHULRU WR FLJDUHWWHV LQ VRPH VLWXDWLRQV LQ WKDW WKH\ HDVLO\ DOORZ WKH SDWLHQW WR VPRNH VPDOO DPRXQWV RI SXUH KLJKJUDGH FDQQDELV 7KH SHUFHQWDJH RI WDUV LQ WKH VPRNH LV UHGXFHG E\ FRQGHQVDWLRQ RQ WKH SLSH ZDOOV 3LSHV VKRXOG EH FOHDQHG IUHTXHQWO\ :DWHU SLSHV DUH LQ IHULRUWRFLJDUHWWHVDQGVKRXOGEHDYRLGHG VHHEHORZ • 7KH XVH RI FDQQDELV WKDW LV IUHH RI QDWXUDO FRQWDPLQDQWV DQG DGXOWHUDQWV 2QO\ GLVHDVHIUHH FDQQDELV VKRXOG EH KDUYHVWHG DQG DLUGULHG *URVV LQ IHFWLRQ ZLWK SDWKRJHQV LV HDVLO\ GHWHFWDEOH 8QJHUOHLGHU HW DO SUR SRVHG WZR PHWKRGV RI VWHULOL]DWLRQ JDVVWHULOL]DWLRQ LQ D PL[ RI HWK\OHQH R[LGH DQG GLFKORURGLIOXRURPHWKDQH DQG VWHULOL]DWLRQ ZLWK &REDOW LUUDGLDWLRQ 1HLWKHU PHWKRG UHGXFHG 7+& FRQWHQW %DNLQJ SODQW PDWHULDO LQ KRPH RYHQV DW & IRU ILYH PLQXWHV NLOOV VSRUHV RI $VSHUJLOOXV IXPLJDWXV $ IODYXV DQG $ QLJHU ZLWKRXW UHGXFLQJ 7+& FRQ WHQW 0F3DUWODQG •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³WRDVWHG´ DSSHDUDQFH ZKHUHDV WKH FRPEXVWHGVDPSOHSURGXFHGWKLFNVPRNHDQGWXUQHGWRDVK • 2PLVVLRQ RI WKH 9DOVDOYD PDQHXYHU DQG SURORQJHG EUHDWKKROGLQJ 6HY HUDO WHFKQLTXHV DUH XVHG WR HQKDQFH 7+& DEVRUSWLRQ LQ WKH OXQJV LQFOXG LQJ WKH 9DOVDOYD PDQHXYHU DQG SURORQJHG EUHDWKKROGLQJ 7KH ILUVW PD\ FDXVH EDURWUDXPD WR WKH OXQJ ZKLOH WKH VHFRQG LQFUHDVHV WKH GHSRVLWLRQ )UDQMR*URWHQKHUPHQ
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• &RPELQDWLRQ RI RUDO XVH DQG LQKDODWLRQ ,Q VHYHUDO LQGLFDWLRQV D FRP ELQHG UHJLPH RI D EDVLF RUDO PHGLFDWLRQ ZLWK FDQQDELV RU 7+& DQG D GH PDQG LQKDOHG PHGLFDWLRQ PD\ EH XVHIXO WR UHGXFH ULVNV IURP VPRNLQJ DQG RYHUGRVDJH ZLWK RUDO DGPLQLVWUDWLRQ 6LPLODU UHJLPHV DUH URXWLQH ZLWK RSLDWHV WR WUHDW FKURQLF DQG EUHDNWKURXJK SDLQ 6WHYHQV DQG *KD]L
5,6.62)25$/86$*(
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³KLJK´ %UHQQHLVHQ HW DO DGPLQLV WHUHG VLQJOH RUDO GRVHV RI RU PJ 7+& WR WZR SDWLHQWV 3K\VLRORJLF SDUDP HWHUV KHDUW UDWH DQG SV\FKRORJLFDO SDUDPHWHUV FRQFHQWUDWLRQ PRRG ZHUH QRWPRGLILHGE\WKHDGPLQLVWUDWLRQ &$11$%,67+(5$3(87,&6,1+,9$,'6
TABLE 2. Dosing-scheme for cannabis taken orally and smoked
Amount of cannabis taken THC content in herbal cannabis 2% THC 5% THC 10% THC oral 0.05 g 1 mg THC 2.5 mg THC 5 mg THC 0.1 g 2 mg THC 5 mg THC 10 mg THC 0.2 g 4 mg THC 10 mg THC 20 mg THC 0.5 g 10 mg THC 25 mg THC 50 mg THC smoking* 1 puff (0.05 g) 1 mg THC 2.5 mg THC 5 mg THC 2 puffs (0.10 g) 2 mg THC 5 mg THC 10 mg THC 4 puffs (0.20 g) 4 mg THC 10 mg THC 20 mg THC 8 puffs (0.40 g) 8 mg THC 20 mg THC 40 mg THC 16 puffs (0.80 g) 16 mg THC 40 mg THC 80 mg THC * Ingested THC was calculated according to the formula: x = amount of cannabis/100 by THC content. It was assumed that an average of 50 mg of cannabis are smoked with one puff, calculated from the following data. Marijuana cigarettes provided by the U.S. National Institute of Drug Abuse (NIDA) weigh about 800 mg (Azorlosa et al. 1992, Azorlosa et al. 1995). Perez-Reyes et al. (1981) noticed that about 24 puffs were necessary to smoke a low-dose NIDA marijuana cigarette, corresponding to 33 mg of cannabis per puff. Liguori et al. (1998) used a smoking regime with 64 mg marijuana per puff. It should be noted that THC be- comes concentrated in the uncombusted parts of a cigarette so that the first puffs yield a little less THC than the later (Tashkin et al. 1991).
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
+$505('8&7,21:,7+25$/86(
7KH PDMRU ULVN DVVRFLDWHG ZLWK RUDO FDQQDELV XVH LV RYHUGRVLQJ 7R DFKLHYH DSSURSULDWHGRVLQJWZRSULQFLSOHVVKRXOGEHIROORZHG )UDQMR*URWHQKHUPHQ
FIGURE 2. Average plasma THC levels (ng/ml) in seven healthy young males following ten puffs from a cannabis cigarette containing 1.75 or 3.55% THC with a breathholding duration of 0, 10, and 20 seconds immediately after smok- ing (drawn according to data from Azorlosa et al. 1995).
160 140 120 100 1.75% THC 80
ng/ml 3.55% THC 60 40 20 0 0 sec 10 sec 20 sec
• $VFHUWDLQPHQWRIRSWLPDOLQGLYLGXDOGRVHE\VORZO\LQFUHDVLQJGRVHV • ,QWDNH RI WKH PHGLFDWLRQ XQGHU WKH FRQVLVWHQW FRQGLWLRQV HVSHFLDOO\ ZLWK UHJDUGWRYHKLFOHDQGILOOLQJRIWKHVWRPDFK • 6XEVHTXHQWDGPLQLVWUDWLRQRIVXSSOHPHQWDOGRVHVE\LQKDODWLRQ
,I SRVVLEOH VORZO\ LQFUHDVLQJ GRVHV VKRXOG EH DSSOLHG LQ D WLWUDWHG IDVKLRQ WR DYRLG XQGHVLUDEOH VLGH HIIHFWV RQ SV\FKH DQG FLUFXODWLRQ 6WDUWLQJ GRVHV DUH ϫ PJ RU ϫ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¶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
75($70(172)$&&,'(17$/29(5'26(
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³7DONLQJ WKH SDWLHQW GRZQ´ PD\ WUHDW G\VSKRULF VWDWHV ,I WKLV SURYHV LQVXI ILFLHQW LQWUDYHQRXV GLD]HSDP PJ PD\ EH DGPLQLVWHUHG 3HUH]5H\HVHW DO )UDQMR*URWHQKHUPHQ
$/7(51$7,9()25062)'(/,9(5<
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³&DQQDELQRLG SDWFK DQG PHWKRG IRU FDQQDELV WUDQVGHUPDO GHOLYHU\´ RQ 6HSWHPEHU 8QLWHG 6WDWHV 3DWHQW 7KH SDWHQW GHVFULEHV D WULDO LQ WZR VXEMHFWV ZKR UHFHLYHG J RI FDQQDELV RLO LQ D FDUULHU '062 7KH SDWFK ZDV DSSOLHG WR WKH XQGHUVLGH RI WKH ZULVW RI WZR KXPDQ VXEMHFWV $FFRUGLQJ WR WKH SDWHQWV VXEMHFWLYH 7+& HIIHFWV ZHUH QRWHG ZLWKLQ WHQ PLQXWHV DQG ODVWHG IRXU WR VL[ KRXUV
620(&203$5,62167223,8023,$7(6
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
35,1&,3/(62)+$505('8&7,21:,7+&$11$%,6
1DWXUDO FDQQDELV LV XVXDOO\ LQKDOHG +RZHYHU WKLV URXWH RI DGPLQLVWUDWLRQ LV RIWHQ XVHG HYHQ LI WKH DGYDQWDJHV RYHU RUDO DSSOLFDWLRQ DUH QRW UHDOO\ RI UHOH YDQFH WR DFKLHYH RSWLPDO WKHUDSHXWLF EHQHILWV ,Q FDVHV ZKHUH LQKDODWLRQ LV WKH EHVW ZD\ WR DGPLQLVWHU FDQQDELV RU VLQJOH FDQQDELQRLGV WHFKQLTXHV GHVLJQHG &$11$%,67+(5$3(87,&6,1+,9$,'6
WR UHGXFH ULVNV WR WKH PXFRVD VKRXOG EH DSSOLHG +DUP UHGXFWLRQ ZLWK UHJDUG WR WKHPHGLFDOXVHRIFDQQDELVPD\LQFOXGHWKHIROORZLQJVWUDWHJLHV
• 5HOLQTXLVKPHQW RI LQKDODWLRQ DQG UHSODFHPHQW E\ RWKHU URXWHV RI DGPLQ LVWUDWLRQLISRVVLEOHRUFRPELQDWLRQRIVHYHUDOURXWHV • 0LQLPL]DWLRQ RI GDPDJH WR WKH UHVSLUDWRU\ WUDFW ZLWK DSSURSULDWH WHFK QLTXHV LQFOXGLQJ WKH XVH RI FDQQDELV ZLWK KLJK 7+& FRQWHQW LQKDODWLRQ ZLWK YDSRUL]HUV DYRLGDQFH RI WKH 9DOVDOYD PDQHXYHU DQG SURORQJHG EUHDWKKROGLQJRYHUVHF • $YRLGDQFH RI DFFLGHQWDO RYHUGRVLQJ WKURXJK WKRURXJK GRVLQJ SURFH GXUHVZLWKRUDOLQJHVWLRQ • 'HYHORSPHQW DQG LPSURYHPHQW RI QRQVPRNHG SDUHQWHUDO DSSOLFDWLRQ IRUPVLQFOXGLQJWKHUHFWDOVXEOLQJXDODQGWUDQVGHUPDOURXWH
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³GR QR KDUP´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
5()(5(1&(6
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|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¶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