- Charged Analogues of Chlorpromazine as Dopamine Antagonists
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Chlorpromazine (1, CPZ) is a potent dopamine antagonist that has been used widely as an antipsychotic agent.Since dopaminergic antagonists, like dopaminergic agonists, exist in solution as the charged and uncharged molecular species, it is not clear which form of the amine is most important for interaction with the dopamine receptor.Previous work from our laboratory has indicated that a variety of permanently charged species could replace the amine/ammonium moiety of dopamine and retain dopamine agonist activity.This paper describes the synthesis and dopamine antagonist activity of both the trimethylammonium iodide (2) and the dimethylsulfonium iodide (3) analogues of chlorpromazine.The permanently uncharged methyl sulfide analogue (4) was also synthesized; however, due to its lack of aqueous solubility, its pharmacological activity could not be evaluated.Binding of both the dimethylsulfonium iodide and the trimethylammonium iodide analogues to D-2 dopamine receptors of rat striatal tissue was observed.The observed relative order of binding was CPZ > CPZ sulfonium analogue > CPZ ammonium analogue.These compounds had a similar order of activity in antagonizing the apomorphine-induced inhibition of potassium-induced release of acetylcholine from mouse striatal slices.
- Harrold, Marc W.,Chang, Yu-An,Wallace, Raye Ann,Farooqui, Tahira,Wallace, Lane J.,et al.
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- Novel phenothiazine antimalarials: Synthesis, antimalarial activity, and inhibition of the formation of β-haematin
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We report the synthesis of a series of novel phenothiazine compounds that inhibit the growth of both chloroquine-sensitive and chloroquine-resistant strains of Plasmodium falciparum. We found that the antimalarial activity of these phenothiazines increased with an increase in the number of basic groups in the alkylamino side chain, which may reflect increased uptake into the parasite food vacuole or differences in the toxicities of individual FP-drug complexes. We have examined the ability of the parent phenothiazine, chlorpromazine, and some novel phenothiazines to inhibit the formation of β-haematin. The degree of antimalarial potency was loosely correlated with the efficacy of inhibition of β-haematin formation, suggesting that these phenothiazines exert their antimalarial activities in a manner similar to that of chloroquine, i.e. by antagonizing the sequestration of toxic haem (ferriprotoporphyrin IX) moieties within the malaria parasite. Chlorpromazine is an effective modulator of chloroquine resistance; however, the more potent phenothiazine derivatives were more active against chloroquine-sensitive parasites than against chloroquine-resistant parasites and showed little synergy of action when used in combination with chloroquine. These studies point to structural features that may determine the antimalarial activity and resistance modulating potential of weakly basic amphipaths.
- Kalkanidis, Martha,Klonis, Nectarios,Tilley, Leann,Deady, Leslie W
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- Chemical synthetic platform for chlorpromazine oligomers that were reported as photo-degradation products of chlorpromazine
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A synthetic platform for chlorpromazine (CPZ) oligomers, which could be generated via photo-reaction of CPZ, is essential to promote their biological and structural studies. In this paper, the first synthetic platform for CPZ oligomers is described. A photo-irradiation experiment of CPZ to confirm whether the structure of the CPZ dimer generated by the photo-irradiation was identical to that prepared by our synthetic method is also reported.
- Kohiki, Taiki,Nishikawa, Yusuke,Inokuma, Tsubasa,Shigenaga, Akira,Otaka, Akira
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- Conjugates Derived from Lapatinib Derivatives with Cancer Cell Stemness Inhibitors Effectively Reversed Drug Resistance in Triple-Negative Breast Cancer
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Increasing evidence indicates that the cancer stem cell (CSC) subpopulation contributes to the therapeutic resistance and metastasis of tumors, leading to patient recurrence and death. Herein, we designed and synthesized several compounds by conjugating lapatinib derivatives with different CSC inhibitors to treat with lapatinib-induced MDA-MB-231 drug-resistant cells. In vitro biological studies indicated that 3a showed strong cytotoxicity and EGFR enzyme inhibitory activity and effectively reversed lapatinib-mediated resistance of MDA-MB-231 cells via inhibiting triple-negative breast cancer (TNBC) cell stemness and the AKT/ERK signaling pathway. In addition, 3a was capable of strongly suppressing the invasion and migration of TNBC cells by inhibiting the Wnt/β-catenin signaling pathway and MMP-2 and MMP-9 protein expression. In vivo tumorigenicity tests showed that 3a could inhibit the occurrence of TNBC by inhibiting BCSCs, proving 3a is a potential EGFR and CSC dual inhibitor for TNBC treatment.
- Wang, Yuanjiang,Lv, Zhaodan,Chen, Feihong,Wang, Xing,Gou, Shaohua
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supporting information
p. 12877 - 12892
(2021/09/13)
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- An Inhibitor of the Interaction of Survivin with Smac in Mitochondria Promotes Apoptosis
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Herein we report the first small molecule that disrupts the survivin-Smac interaction taking place in mitochondria. The inhibitor, PZ-6-QN, was identified by initially screening a phenothiazine library using a fluorescence anisotropy assay and then conducting a structure–activity relationship study. Mutagenesis and molecular docking studies suggest that PZ-6-QN binds to survivin similarly to the known Smac peptide, AVPI. The results of the effort also show that PZ-6-QN exhibits good anticancer activity against various cancer cells. Moreover, cell-based mechanistic studies provide evidence for the proposal that PZ-6-QN enters mitochondria to inhibit the survivin-Smac interaction and promotes release of Smac and cytochrome c from mitochondria into the cytosol, a process that induces apoptosis in cancer cells. Overall, the present study suggests that PZ-6-QN can serve as a novel chemical probe for study of processes associated with the mitochondrial survivin-Smac interaction and it will aid the discovery of novel anticancer agents.
- Park, Seong-Hyun,Shin, Insu,Park, Sang-Hyun,Kim, Nam Doo,Shin, Injae
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supporting information
p. 4035 - 4041
(2019/08/02)
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- Reversed isoniazids: Design, synthesis and evaluation against Mycobacterium tuberculosis
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Novel reversed isoniazid (RINH) agents were synthesized by covalently linking isoniazid with various efflux pump inhibitor (EPI) cores and their structural motifs. These RINH agents were then evaluated for anti-mycobacterial activity against sensitive, isoniazid mono-resistant and MDR clinical isolates of M. tuberculosis and a selected number of compounds were also tested ex vivo for intracellular activity as well as in the ethidium bromide (EB) assay for efflux pump inhibition efficacy. The potency of some compounds against various strains of M. tuberculosis (4a–c, 7 and 8; H37Rv-MIC99 ≤1.25 μM, R5401-MIC99 ≤2.5 μM, X_61-MIC99 ≤5 μM) demonstrated the potential of the reversed anti-TB agent strategy towards the development of novel anti-mycobacterial agents to address the rapidly growing issue of resistance. Further, macrophage activity with >90% inhibition by 1a–c and 3b (MIC90 ≤13.42 μM) and inhibition of EB efflux demonstrated by these compounds are encouraging.
- Kumar, Malkeet,Singh, Kawaljit,Ngwane, Andile H.,Hamzabegovic, Fahreta,Abate, Getahun,Baker, Bienyameen,Wiid, Ian,Hoft, Daniel F.,Ruminski, Peter,Chibale, Kelly
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supporting information
p. 833 - 844
(2018/01/22)
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- The phenothiazine compound and its preparation method and application
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The invention relates to a phenothiazine compound and a preparation method thereof. The invention further relates the application of the phenothiazine compound in anti-cancer drug preparation and anti-cancer drugs using the compound as the effective component. The phenothiazine compound has the advantages that the compound with broad-spectrum anti-cancer effect is obtained by modifying phenothiazine ternary interlink parent nucleuses, synthesizing method is simple, and high yield is achieved; the phenothiazine compound has certain restraining effect on human breast cancer cells line MCF-7 and human hepatoma cell line Hep-G2, and a new thought is provided to new drugs satisfying clinic requirements.
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Paragraph 0122-0125
(2018/07/30)
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- A preparation method of the third chlorine pulls qin
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The invention discloses a method for preparing the third chlorine pulls qin, has changed the existing method of the reaction sequence, the first to use 1 - bromo - 3 - chloro propane and 2 - chloro phenothiazine reaction, further with the third chlorine pulls qin N - methyl piperazine is generated by the reaction. This invention discloses technology can not complete reaction lead to reaction the cost is high, and has a gene toxic impurities to make the final purity of the product is difficult to achieve the medical-grade technical defect.
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Paragraph 0026; 0027; 0030
(2018/10/11)
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- Repositioning of the antipsychotic trifluoperazine: Synthesis, biological evaluation and in silico study of trifluoperazine analogs as anti-glioblastoma agents
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Repositioning of the antipsychotic drug trifluoperazine for treatment of glioblastoma, an aggressive brain tumor, has been previously suggested. However, trifluoperazine did not increase the survival time in mice models of glioblastoma. In attempt to identify an effective trifluoperazine analog, fourteen compounds have been synthesized and biologically in vitro and in vivo assessed. Using MTT assay, compounds 3dc and 3dd elicited 4–5 times more potent inhibitory activity than trifluoperazine with IC50 = 2.3 and 2.2 μM against U87MG glioblastoma cells, as well as, IC50 = 2.2 and 2.1 μM against GBL28 human glioblastoma patient derived primary cells, respectively. Furthermore, they have shown a reasonable selectivity for glioblastoma cells over NSC normal neural cell. In vivo evaluation of analog 3dc confirmed its advantageous effect on reduction of tumor size and increasing the survival time in brain xenograft mouse model of glioblastoma. Molecular modeling simulation provided a reasonable explanation for the observed variation in the capability of the synthesized analogs to increase the intracellular Ca2+ levels. In summary, this study presents compound 3dc as a proposed new tool for the adjuvant chemotherapy of glioblastoma.
- Kang, Seokmin,Lee, Jung Moo,Jeon, Borami,Elkamhawy, Ahmed,Paik, Sora,Hong, Jinpyo,Oh, Soo-Jin,Paek, Sun Ha,Lee, C. Justin,Hassan, Ahmed H.E.,Kang, Sang Soo,Roh, Eun Joo
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p. 186 - 198
(2018/04/05)
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- Chemical synthetic platform for chlorpromazine oligomers that were reported as photo-degradation products of chlorpromazine
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A synthetic platform for chlorpromazine (CPZ) oligomers, which could be generated via photo-reaction of CPZ, is essential to promote their biological and structural studies. In this paper, the first synthetic platform for CPZ oligomers is described. A photo-irradiation experiment of CPZ to confirm whether the structure of the CPZ dimer generated by the photo-irradiation was identical to that prepared by our synthetic method is also reported.
- Kohiki, Taiki,Nishikawa, Yusuke,Inokuma, Tsubasa,Shigenaga, Akira,Otaka, Akira
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p. 1161 - 1166
(2018/05/02)
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- Chemical synthetic platform for chlorpromazine oligomers that were reported as photo-degradation products of chlorpromazine
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A synthetic platform for chlorpromazine (CPZ) oligomers, which could be generated via photo-reaction of CPZ, is essential to promote their biological and structural studies. In this paper, the first synthetic platform for CPZ oligomers is described. A photo-irradiation experiment of CPZ to confirm whether the structure of the CPZ dimer generated by the photo-irradiation was identical to that prepared by our synthetic method is also reported.
- Kohiki, Taiki,Nishikawa, Yusuke,Inokuma, Tsubasa,Shigenaga, Akira,Otaka, Akira
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p. 1161 - 1161
(2019/12/26)
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- Synthesis and SAR evaluation of novel thioridazine derivatives active against drug-resistant tuberculosis
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The neuroleptic drug thioridazine has been recently repositioned as possible anti-tubercular drug. Thioridazine showed anti-tubercular activity against drug resistant mycobacteria but it is endowed with adverse side effects. A small library of thioridazine derivatives has been designed through the replacement of the piperidine and phenothiazine moieties, with the aim to improve the anti-tubercular activity and to reduce the cytotoxic effects. Among the resulting compounds, the indole derivative 12e showed an antimycobacterial activity significantly better than thioridazine and a cytotoxicity 15-fold lower.
- Scalacci, Nicolò,Brown, Alistair K.,Pavan, Fernando R.,Ribeiro, Camila M.,Manetti, Fabrizio,Bhakta, Sanjib,Maitra, Arundhati,Smith, Darren L.,Petricci, Elena,Castagnolo, Daniele
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p. 147 - 158
(2016/12/30)
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- Overcoming chloroquine resistance in malaria: Design, synthesis, and structure-activity relationships of novel hybrid compounds
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Resistance to antimalarial therapies, including artemisinin, has emerged as a significant challenge. Reversal of acquired resistance can be achieved using agents that resensitize resistant parasites to a previously efficacious therapy. Building on our initial work describing novel chemoreversal agents (CRAs) that resensitize resistant parasites to chloroquine (CQ), we herein report new hybrid single agents as an innovative strategy in the battle against resistant malaria. Synthetically linking a CRA scaffold to chloroquine produces hybrid compounds with restored potency toward a range of resistant malaria parasites. A preferred compound, compound 35, showed broad activity and good potency against seven strains resistant to chloroquine and artemisinin. Assessment of aqueous solubility, membrane permeability, and in vitro toxicity in a hepatocyte line and a cardiomyocyte line indicates that compound 35 has a good therapeutic window and favorable drug-like properties. This study provides initial support for CQ-CRA hybrid compounds as a potential treatment for resistant malaria.
- Boudhar, Aicha,Ng, Xiao Wei,Loh, Chiew Yee,Chia, Wan Ni,Tan, Zhi Ming,Nosten, Francois,Dymock, Brian W.,Tan, Kevin S. W.
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p. 3076 - 3089
(2016/05/11)
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- Incorporation of triphenylphosphonium functionality improves the inhibitory properties of phenothiazine derivatives in Mycobacterium tuberculosis
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Tuberculosis (TB) is a difficult to treat disease caused by the bacterium Mycobacterium tuberculosis. The need for improved therapies is required to kill different M. tuberculosis populations present during infection and to kill drug resistant strains. Protein complexes associated with energy generation, required for the survival of all M. tuberculosis populations, have shown promise as targets for novel therapies (e.g., phenothiazines that target type II NADH dehydrogenase (NDH-2) in the electron transport chain). However, the low efficacy of these compounds and their off-target effects has made the development of phenothiazines as a therapeutic agent for TB limited. This study reports that a series of alkyltriphenylphosphonium (alkylTPP) cations, a known intracellular delivery functionality, improves the localization and effective concentration of phenothiazines at the mycobacterial membrane. AlkylTPP cations were shown to accumulate at biological membranes in a range of bacteria and lipophilicity was revealed as an important feature of the structure-function relationship. Incorporation of the alkylTPP cationic function significantly increased the concentration and potency of a series of phenothiazine derivatives at the mycobacterial membrane (the site of NDH-2), where the lead compound 3a showed inhibition of M. tuberculosis growth at 0.5 μg/mL. Compound 3a was shown to act in a similar manner to that previously published for other active phenothiazines by targeting energetic processes (i.e., NADH oxidation and oxygen consumption), occurring in the mycobacterial membrane. This shows the enormous potential of alkylTPP cations to improve the delivery and therefore efficacy of bioactive agents targeting oxidative phosphorylation in the mycobacterial membrane.
- Dunn, Elyse A.,Roxburgh, Marina,Larsen, Lesley,Smith, Robin A.J.,McLellan, Alexander D.,Heikal, Adam,Murphy, Michael P.,Cook, Gregory M.
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p. 5320 - 5328
(2014/12/10)
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- Synthesis and pharmacological characterization of novel inverse agonists acting on the viral-encoded chemokine receptor US28
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G-protein coupled receptors encoded by viruses represent an unexplored class of potential drug targets. In this study, we describe the synthesis and pharmacological characterization of the first class of inverse agonists acting on the HCMV-encoded receptor US28. It is shown that replacement of the 4-hydroxy group of lead compound 1 with a methylamine group results in a significant 6-fold increase in affinity. Interestingly, increasing the rigidity of the spacer by the introduction of a double bond also leads to a significant increase in binding affinity compared to 1. These novel inverse agonists serve as valuable tools to elucidate the role of constitutive signaling in the pathogenesis of viral infection and may have therapeutic potential as leads for new antiviral drugs.
- Hulshof, Janneke W.,Vischer, Henry F.,Verheij, Mark H.P.,Fratantoni, Silvina A.,Smit, Martine J.,de Esch, Iwan J.P.,Leurs, Rob
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p. 7213 - 7230
(2007/10/03)
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- Identification of a non peptidic RANTES antagonist
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A series of phenothiazines demonstrating inhibition of RANTES binding to THP-1 cell membranes has been identified. The lead compound RP23618 (IC50 = 3 μM) was found to inhibit specific binding of 125I-RANTES, but not 125I-MCP-1 to THP-1 cell membranes and furthermore to antagonise RANTES, but not MCP-1-induced chemotaxis of THP-1 cells.
- Bright, Colin,Brown, Thomas J.,Cox, Paul,Halley, Frank,Lockey, Peter,McLay, Iain M.,Moore, Una,Porter, Barry,Williams, Robert J.
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p. 771 - 774
(2007/10/03)
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- Synthesis of spin labels for ESR imaging of living rat head
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Spin labels (7, 10, 13, 16, 22, 27) were synthesized from piperidinyloxyl (1), pyrrolidinyloxyl (2), and oxazolidinyloxyl (3). These compounds were injected into the carotid artery of anesthetized rats, and the ESR spectra of the rat brain were immediately recorded by the use of an L- band ESR spectrometer. Based on the spectra obtained, we considered whether or not these spin labels can pass the blood brain barrier and bind to brain tissue components.
- Niwa, Ryuji,Konaka, Ryusei,Hiramatsu, Midori,Kamada, Hitoshi
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p. 923 - 927
(2007/10/03)
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- Agmatine for the treatment of neurotrauma and neurodegenerative diseases
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The invention relates to the use of agmatine, in the treatment of acute neurotrauma (such as stroke) and degenerative disorders of the central and peripheral nervous system (such as dementia).
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- Heterocyclic compounds
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A compound of formula (I): STR1 in which X, n, B and Y are as defined in the description. useful as cytokine inhibitors.
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- Tests of a Piperidino Mask for the Protection of Functionalized Carbon Sites in Multistep Syntheses
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Primary alkyl chlorides (R-Cl) are easily isolated in excellent yield after treatment of the appropriate N-alkylpiperidines (R-NC5H10) with α-chloroethyl chloroformate.The method is exemplified by the conversion of a variety of alkylpiperidines, including systems with other sensitive functionalities, to the respective chlorides in yields varying from 90 to 97percent.The potential significance of this process in drug congener preparation and in total synthesis is outlined.Similar fragmentations of N-sec-alkylpiperidines are described.
- Olofson, R. A.,Abbott, Duain E.
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p. 2795 - 2799
(2007/10/02)
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- (1-(3-(Phenothiazin-10-yl)propyl)-4-piperidinyl)phenylmethanones, a novel class of long-acting neuroleptic agents.
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In previous studies the phenyl-4-piperidinylmethanone moiety was shown to be a neuroleptic pharmacophore. A short series of [1-[3-(phenothiazin-10-yl)propyl]-4-piperidinyl]phenylmethanones was prepared and tested for neuroleptic activity using the blockade of d-amphetamine lethality in aggregated mice and suppression of conditioned avoidance behavior as the end points. Most compounds were shown to be potent neuroleptic agents and two were found to possess a long duration of action.
- Boswell Jr.,Welstead Jr.,Duncan Jr.,Johnson,Funderburk
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p. 136 - 139
(2007/10/05)
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