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��ࡱ�>��	WY����V���������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������[�	����bjbj����	4�ΐΐ�W+���������55555����III8��=$II@a~����888yH{H{H{H{H{H{H$^K�N:�H9588888�H55��C�H�-�-�-8|5�5�yH�-8yH�-�-6�C�)F������'y�c#�I�)xeDeH�H0I�D�:N,+�:N8)F:N5)F<88�-88888�H�H�-888I8888��������������������������������������������������������������������:N888888888�	�:	Review Article
Bronchodilator and positive inotropic activity of pyridazine compound Zardaverine as a Phosphodiesterase isozymes inhibitor
Mohammad Asif
Department of Pharmacy, GRD (PG) IMT, Dehradun, 248009 Uttarakhand, India

Abstract-The pyridazinone compound zardaverine has been launched as a potent bronchodilator and also uses as positive inotropic agent. The effects of zardaverine are mediated via inhibition of phasphodiestrase (PDE) activity. There are many forms of PDE isoenzymes. The activities of zardaverine on the different PDE isozymes were investigated. Zardaverine inhibited the cyclic GMP-inhibitable PDE III from human platelets and the rolipram-inhibitable PDE-IV from canine trachea and human polymorphonuclear (PMN) cells. The Zardaverine affected the calmodulin-stimulated PDE-I, the cyclic GMP-stimulated PDE-II and the cyclic GMP-specific PDE-V only marginally at concentrations up to 100 �M. Zardaverine inhibits the ADP-induced aggregation of human platelets. This inhibition was synergistically increased by activators of adenylate cyclase such as PGE1 and forskolin. In human PMN cells, zardaverine inhibited the zymosan-induced superoxide anion generation. Again, this effect was increased by activators of adenylate cyclase. The zardaverine is a selective inhibitor of PDE-III and PDE-IV isozymes. 

Key words: pyridazinone, zardaverine, phosphodiesterase, bronchodilator

Introduction: In recent years large numbers of pyridazinone compounds have been reported to possess almost all type biological activities viz. antimicrobial, analgesic, anti-inflammatory, antifeedant, herbicidal, anticancer, antiphlogistics, antipyretics, antisecretory, antiulcer, antidepressants, neuroleptics, anxiolytics, sedative-hypnotics, tranquillizers, anticonvulsants, GABA antagonists, immunosuppressant and other anticipated biological and pharmacological properties.[1-5] In particular, a large number of pyridazinone derivatives are also well known as intermediates for drugs and agrochemicals agents. The cardiovascular activities of pyridazine compounds are very well know. These cardiovascular activities are mainly blood platelet aggregation inhibitors, antihypertensive, antithrombotics, cardiotonics, vasodilatators, antiarrhythmics, selective �-blockers, and hypocholesterolaemic.[6,7]
Cyclic nucleotides mediate many different effects in mammalian cells such as hydrolysis of 3',5'-cyclic nucleotides to the corresponding nucleoside 5'-monophosphates and regulate the cyclic nucleotide concentrations. The advance of PDE inhibitors to increase intracellular cyclic nucleotide intensity characterizes an important pharmacological action to dealing of a number of diseases. The PDE inhibitors may have potential therapeutic significance, including heart failure, obstructive airways disease, thrombosis, hypertension and inflammation.[8] The PDE inhibitors have been used therapeutically for many years and their effectiveness has been restricted by side effects and low potency. Multiple molecular forms of PDEs have been identified in various tissues, like cardiac muscle, platelets, and tracheal smooth muscle.[8,9] 

Zardaverine acts as phosphodiesterase III and IV Inhibitor: 
The pyridazinone compound zardaverine (6-(4-difluoromethoxy-3-methoxy-phenyl)-3(2H)pyridazinone) (Figure 1) has been commenced as a potent bronchodilator and inotropic agent. The zardaverine act by inhibited of phosphodiesterase (PDE) enzymes[10-12]. The action of  zardaverine on the different PDE isozymes in some tissues. Zardaverine inhibited the cyclic GMP-inhibitable PDE-III from human platelets and the rolipram-inhibitable PDE-IV from canine trachea and human polymorphonuclear (PMN) cells. Zardaverine also affected the calmodulin-stimulated PDE-I, the cGMP-stimulated PDE-II and the cGMP-specific PDE-V only slightly at concentrations up to 100�M. Zardaverine inhibits the ADP-induced aggregation of human platelets and this inhibition was synergistically improved by activators of adenylate cyclase such as PGE1 and forskolin. In human, zardaverine inhibited the zymosan-induced superoxide anion generation and this action was increased by activators of adenylate cyclaseHYPERLINK "javascript:PopUpMenu2_Set(Menu7912931);" \t "_self"HYPERLINK "javascript:PopUpMenu2_Set(Menu6543308);" \t "_self"HYPERLINK "javascript:PopUpMenu2_Set(Menu7912931);" \t "_self". It will be possible to develop selective and possibly therapeutically useful PDE inhibitors that can be targeted for specific tissues. The concentrations for the inotropic effects of zardaverine are about 10 times more than those for bronchodilatation . The compound increases intracellular cyclic AMP concentrations via an inhibition of PDE activity.[10-15] 
 EMBED ChemDraw.Document.6.0 
Figure 1. Structure of Zardaverine                        
The PDE isozymes differ in their kinetic and physical characteristics, substrate specificities, tissue distribution and subcellular localization [15]. The function of these different enzymes and their involvement in regulation of signal transfer within cells is poorly understood. Some of the isozyme families inhibitors have been created that possess isozyme selectivity.[9] Some of these selective inhibitors are used pharmacologically. The inhibitory potency of zardaverine on selected PDE isozymes, PDE activities representing the five isozymes. In platelets, homogenates were used as an enzyme source, only one isozyme is chiefly active. The PDE-IB from bovine brain, which is calmodulin-sensitive and displays selectivity for cGMP [16]; cGMP-stimulated PDE-II obtained from cardiac ventricle; PDE-III obtained from cardiac ventricle and human platelets; the PDE-IV, the isozymes from cardiac ventricle and canine trachea were used; the cGMP specific PDE-V was obtained from human platelets.[17-19] The inhibition of PDE-III activity from human platelets and PDE-IV from canine trachea in various concentrations of zardaverine, demonstrated a slightly higher affinity of zardaverine for PDE-IV compared to PDE-III. The potency of zardaverine and other agents as inhibitors of the different PDE isozymes, in contrast to PDE III and IV, activities of PDE I, II and V were affected only at zardaverine concentrations above 100�M. Thus, zardaverine exhibits at least 100-fold selectivity for PDE-III and PDE-IV over PDE-I, PDE-II and PDE-V. A similar selectivity is found for another pyridazinone derivative, B832-07, but at variance, this compound is about 30-fold more potent as inhibitor of PDE-III than as inhibitor of PDE-IV. However, B832-145, a third compound of this class, exhibits remarkable PDE-IV selectivity as compared to zardaverine.[20,21] The pharmacological effects of the various PDE inhibitors were evaluated by using human platelets and PMN, determine the synergistic interactions between PDE inhibitors and activators of adenylate cyclase. The zardaverine inhibited aggregation of platelets induced by a variety of different agonists such as ADP, PAF, collagen and arachidonic acid. The zardaverine was inhibitied platelet aggregation in the range of 1.5 to 16.2 �M. The anti-aggregatory potency of zardaverine was markedly increased in the presence of activators of adenylate cyclase and consistent with a synergistic interaction between zardaverine and activators of adenylate cyclase. Compared to zardaverine, B832-07 was approximately three-fold more potent and B832-145 approximately two-fold less potent as inhibitors of platelet aggregation. The xanthines IBMX, theophylline and enprofylline were only weak inhibitors of platelet aggregation with IC50 values of 17.8, 316 and 50�M, respectively.[14] 
Superoxide anion generation stimulated by opsonized zymosan was time and dose dependent. In the absence of any activator of adenylate cyclase, zardaverine inhibited zymosan-induced O2-release. Both forskolin and PGE2 synergistically increased the inhibitory potency of zardaverine in a concentration-dependent manner. However, the combined effects of the adenylate cyclase activator and zardaverine do not significantly differ from the additive mode and a complex interaction between zardaverine and these cells. With both platelets and PMN cells, there was no significant difference in the release of LDH in the presence or absence of any PDE inhibitor, indicating that none of the compounds were cytotoxic. The inhibition of platelet aggregation, the xanthines IBMX, theophylline and enprofylline were rather weak inhibitors of O2-release. The motapizone in PMN cells was about 18,000-fold higher than that for inhibition of platelet aggregation. Milrinone was about 300-fold, CI 930 about 500- fold, and B832-07 about 20-fold less potent as inhibitors of O2- release than as inhibitors of platelet aggregation. In contrast, rolipram and Ro 20-1724 was about 700- fold more potent in PMN cells than in platelets. The inhibition of PDE isozymes with the functional experiments on the cellular level and reveal a high correlation between inhibition of aggregation and PDE-III inhibition and between inhibition of O2-release and PDE-IV inhibition.[14] 
Several distinct isozymes were used to evaluate the selectivity of zardaverine for PDE isozymes. Both PDE III and IV were found to be present in homogenates of tracheal tissue.[21,22] These two isozymes, the cGMP-inhibited PDE-III and the cAMP-specific PDE-IV, have been the mainly focus of research[9,23] The inhibition of PDE-III and PDE-IV, the results indicated that three groups of PDE III/IV inhibitors can be differentiated: 
compounds such as motapizone, milrinone and CI 930 with selectivity for PDE-III; 
PDE-IV selective inhibitors such as rolipram and Ro 20-1724
a third group of compounds combine both PDE-III and PDE-IV inhibitor activity, e.g. zardaverine. 
The zardaverine inhibits PDE III and PDE IV activities with 1c50 values ranging from 0.56 to 1.7�M and shows, an 80-1700-fold selectivity for these isozymes compared to PDE-I, PDE-II and PDE-V.  The zardaverine show a slight preference for inhibition of the PDE-IV subtype over that of the PDE-III subtype. Whether PDE-III or PDE-IV isozymes present in different human tissues will be inhibited with similar potency or will differentiate into further subtypes remains to be clarified.[22,24] The mucosal tissue contains PDE IV preferentially, since in eluates from isolated smooth muscle tissue the peaks of PDE-III and PDE-IV. It was shown that a number of PDE inhibitors with selectivity for either PDE-III or PDE-IV were comparably capable of inducing relaxation or preventing agonist-induced constriction. The presence of both isozymes in human tracheal smooth muscle[25], the inhibition of both PDE-III and PDE -IV isozymes by zardaverine could correlate to a bronchodilator action. The presence of a PDE isozyme in a tissue homogenate does not confirm that it is important for the regulation of cAMP content in intact cells. The synergistic interactions between PDE inhibitors and activators of adenylate cyclase, zardaverine inhibited platelet aggregation regardless of the aggregatory agent with IC50 values ranging from 1.5 to 16�M. Zardaverine inhibited zymosan-induced superoxide anion release from PMN cells with an IC50 of 0.6�M. Zardaverine is, approximately three times more potent in PMN cells than in platelets. In both platelets and PMN cells, combining any activator of adenylate cyclase with zardaverine resulted in a marked increase of the PDE inhibitor activity. In platelets zardaverine and the activators of adenylate cyclase act synergistically to increase cAMP content, whereas in PMN cells a more complex interaction might be present. Thus, as a consequence of the synergistic interaction between a PDE inhibitor and an endogenous activator of adenylate cyclase such as epinephrine or PGE2, plasma concentrations Zardaverine as a selective inhibitor of PDE inhibitors that are considerably lower than IC50 values for PDE inhibition may produce increases in cAMP content in target cells, thereby  inhibiting or preventing cell activation. Based on the inhibition of platelet aggregation and of superoxide anion release from PMN cells by PDE inhibitors, the functional role of the individual PDEs can also be determined.[14] Inhibitors with selectivity for PDE III were potent in platelets, whereas those with selectivity for PDE-IV were potent inhibitors of O2-release in PMN cells. It can be concluded, therefore, that with respect to the particular response, PDE-III is important for regulating cyclic AMP content in human platelets, whereas PDE-IV is the predominant isozyme in PMN cells. Zardaverine does not have an inhibitory effect only on PMN ceils-but also influences the function of other inflammatory cells. The zardaverine and rolipram inhibited zymosan-induced O2- production. A significant inhibition was observed at 0.1�M zardaverine. In contrast, selective PDE-III inhibitors did not affect cell activation at concentrations up to 100�M. Therefore, inhibition of O2-release from eosinophils seems to be mediated by PDE-IV. A synergism between zardaverine and salbutamol was observed in human eosinophils []. The zardaverine also possesses the prerequisites to inhibit activation of proinflammatory cells and could possibly be regarded as an anti-inflammatory drug. With respect to the treatment of inflammatory diseases such as asthma zardaverine could represent a anti-obstructive drugs that, by virtue of inhibition of PDE-III and PDE-IV isozymes, possess bronchodilator and anti-inflammatory activities.[14, 26-28] 

Conclusion: The structural feature of pyridazine compounds exhibited many biologically active compounds with diverse pharmacological activities. Pyridazines hold considerable interest relative to the preparation of organic drug intermediates and physiologically active compounds. However, some compounds bearing pyridazinone rings have been reported as cardiovascular drugs. [29-30] Pyridazinones focused our attention because of their easy functionalization which makes them attractive compounds for designing and development of new drugs in future. These activities prompted us to study pyridazinone compounds with cardiac activity.

References 
Asif M. Some recent approaches of biologically active substituted pyridazine and phthalazine drugs.  Curr Med Chem, 2012, 19(18), 2984-2991.
Asif M, Singh A, Lakshmayya. The development of structurally different new antitubercular molecules containing pyridazine ring system in Chronicle of young scientist. 2013, 4(1): 1-8.
Asif M, Singh A, Ratnakar L. Antimicrobial agents: brief study of pyridazine derivatives against some phathogenic microrganisms. J Pharm Res, 2011, 4(3): 664-667.
Asif M. Anticonvulsant and comparative structure activity relationship of pyridazine derivatives with currently clinically used anticonvulsants. J Adv Sci Res, 2010, 1(1): 35-45.
Asif M. Antifeedant, herbicidal and molluscicidal activities of pyridazinone compounds. Mini Rev Org Chem, 2013, 10(2): 113-122.
Asif M, Anita Singh A, Siddiqui AA. The effect of pyridazine compounds on the cardiovascular system. Med Chem Res. 2012, 21: 3336�3346.
Asif M. General study of pyridazine compounds against cyclooxygenase enzyme and their relation with analgesic, anti-inflammatory and anti-arthritic activities. Chron Young Sci, 2010, 1(3): 3-9. 
Pang DC. Cyclic AMP and cyclic GMP phospho- diesterases: Target for drug development. Drug Dev Res, 1988,12: 85-92. 
Beavo JA, Reifsnyder DH. Primary sequence of cyclic nucleotide phosphodiesterase isozymes and the design of selective inhibitors. Trends Pharmacol Sci, 1990, 11: 150-155. 
Kilian U, Beume R, Eltze M, Schudt C. Is phosphodiesterase inhibition a relevant bron- chospasmolytic principle? Agents Actions, 1989, (Suppl 28): 331-348. 
Beume R, Eltze M, Kilian U. Bronchodilation due to inhibition of cAMP-PDE III: preclinical results on the pyridazinone derivative B842-90. Naunyn Schmiedbergs Arch Pharmacol, 1987, 335: R76. 
Galvan M, Schudt C. Actions of the phosphodiesterase inhibitor zardaverine on guinea-pig ven- tricular muscle. Naunyn Schmiedbergs Arch Pharmacol, 1990,342: 221-227.
HYPERLINK "javascript:PopUpMenu2_Set(Menu7912931);" \t "_self"HYPERLINK "javascript:PopUpMenu2_Set(Menu6543308);" \t "_self"HYPERLINK "javascript:PopUpMenu2_Set(Menu7912931);" \t "_self"HYPERLINK "javascript:PopUpMenu2_Set(Menu7912931);" \t "_self"HYPERLINK "javascript:PopUpMenu2_Set(Menu6543308);" \t "_self"HYPERLINK "http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=Search&Term=%22Ishimori%20T%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_DiscoveryPanel.Pubmed_RVAbstractPlus"Ishimori T, HYPERLINK "http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=Search&Term=%22Gotanda%20K%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_DiscoveryPanel.Pubmed_RVAbstractPlus"Gotanda K, HYPERLINK "http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=Search&Term=%22Sasaki%20T%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_DiscoveryPanel.Pubmed_RVAbstractPlus"Sasaki T, HYPERLINK "http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=Search&Term=%22Shinbo%20A%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_DiscoveryPanel.Pubmed_RVAbstractPlus"Shinbo A, HYPERLINK "http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=Search&Term=%22Asano%20H%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_DiscoveryPanel.Pubmed_RVAbstractPlus"Asano H, HYPERLINK "http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=Search&Term=%22Miyazawa%20K%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_DiscoveryPanel.Pubmed_RVAbstractPlus"Miyazawa K, HYPERLINK "http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=Search&Term=%22Miyasaka%20K%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_DiscoveryPanel.Pubmed_RVAbstractPlus"Miyasaka K. HYPERLINK "javascript:PopUpMenu2_Set(Menu7912931);" \t "_self"Cardiac effects of the novel pyridazinone derivative 6-[4-[2-[3-(5-chloro-2-cyanophenoxy)-2-hydroxypropyl amino]-2-methylpropylamino] phenyl]-4,5-dihydro-5-methyl-3(2H)pyridazinone mono ethyl maleate and its metabolite in isolated heart preparations of guinea pigs and dogs. Arzneimittelforschung, 1994, 44(5): 583-8.
HYPERLINK "http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=Search&Term=%22Schudt%20C%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_DiscoveryPanel.Pubmed_RVAbstractPlus"Schudt C, HYPERLINK "http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=Search&Term=%22Winder%20S%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_DiscoveryPanel.Pubmed_RVAbstractPlus"Winder S, HYPERLINK "http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=Search&Term=%22M%C3%BCller%20B%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_DiscoveryPanel.Pubmed_RVAbstractPlus"M�ller B, HYPERLINK "http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=Search&Term=%22Ukena%20D%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_DiscoveryPanel.Pubmed_RVAbstractPlus"Ukena D. Zardaverine as a selective inhibitor of phosphodiesterase isozymes. Biochem Pharmacol, 1991, 42(1): 153-62.
Weishaar RE, Burrows SD, Kobylarz DC, Quade MM, Evans DB, Multiple molecular forms of cyclic nucleotide phosphodiesterase in cardiac and smooth muscle and in platelets. Biochem Pharmacol, 1986, 35: 787- 800. 
Gietzen K, Sadorf I, Bader H, A model for the regulation of the calmodulin-dependent enzymes erythrocyte Ca2+-transport ATPase and brain phosphodiesterase by activators and inhibitors. Biochem J, 1982, 207: 541-548. 
Reeves ML, Leigh BK, England PJ. The identification of a new cyclic nucleotide phosphodiesterase activity in human and guinea-pig cardiac ventricle. Biochem J, 1987, 241: 535-541. 
Silver PJ, Hamel LT, Perrone MH, Bentley RG, Bushover CR, Evans DB, Differential phar- macologic sensitivity of cyclic nucleotide phosphodiesterase isozymes isolated from cardiac muscle, arterial and airway smooth muscle. Eur J Pharmacol, 1988, 150: 85-94. 
Simpson AWM, Reeves ML, Rink TJ. Effects of SK&F 94120, and inhibitor of cyclic nucleotide phosphodiesterase type III, on human platelets. Biochem Pharmacol, 1988, 37: 2315-2320. 
Kilian U, Amschler H, Beume R, Eltze M, Kolassa N, Schudt C, Bronchospasmolytic effects of substituted 6-phenyl-3 (2H)-pyridazinones in comparison to  theophylline and enprofylline. In: Anti-asthma Xan- thines and Adenosine (Eds. Andersson K-E and Persson CGA), pp. 209-213. Excerpta Medica, Amsterdam, 1985. 
Torphy TJ, Cieslinski LB. Characterization and selective inhibition of cyclic nucleotide phosphodiesterase isozymes in canine tracheal smooth muscle.  Mol Pharmacol, 1989, 37: 206-214. 
Weishaar RE, Kobylarz-Singer DC, Steffen RP, Kaplan HR. Subclasses of cyclic AMP-specific phosphodiesterase in left ventricular muscle and their involvement in regulating myocardial contractility. Circ. Res, 1987, 61: 539-547. 
Harrison SA, Chang ML, Beavo JA. Differential inhibition of cardiac cyclic nucleotide phospho- diesterase isozymes by cardiotonic drugs. Circulation  73 (Suppl III): 109-116, 1986.
Weishaar RE, Kobylarz-Singer DC, Kaplan HR, Subclasses of cyclic AMP phosphodiesterase in cardiac muscle. J Mol Cell Cardiol, 1987, 19: 1025-1036. 
Cieslinski LB, Reeves ML, Torphy TJ. Cyclic nucleotide phosphodiesterases (PDEs) in canine and human tracheal smooth muscle (tsm). FASEB J, 1988, 2: A1065. 
Dent G, Rabe K, Giembycz MA, Barnes PJ. Inhibition of eosinophil respiratory burst activity by type IV-, but not type III-selective cAMP phosphodiesterase inhibitors. Am Respir Dis, 1990, 141: A878.
Elliot KEF, Berry JL, Bate AJ, Foster RW, Small RC. The isozyme selectivity of AH 21-132 as an inhibitor of cyclicnucleotide phosphodiesterase activity. J Enzyme Inhibition, 1991,4: 245-251. 
Beavo JA, Multiple isozymes of cyclic nucleotide phosphodiesterase. Ado Second Messengers Phos- phoprotein Res, 1988, 22: 1-38. 
Asif M. Recent Approaches toward anticonvulsant activity of pyridazine compounds. Open J Org Chem56?MUe���������̺ߨ������ufWG5"h9:�h�5�CJOJQJ\�aJh�xph�5�CJOJQJaJh�xph�CJOJQJaJh�5�CJOJQJ\�aJhA^�5�CJOJQJ\�aJ"h9:�h�Oi5�CJOJQJ\�aJ"h9:�hko�5�CJOJQJ\�aJ"h9:�h�	5�CJOJQJ\�aJ"h9:�h�	5�CJOJQJ]�aJ%h9:�h�	5�6�CJOJQJ]�aJh9:�h�	5�CJOJQJaJh9:�h6<5�CJOJQJaJ����5
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