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Volume 56, Issue 12
Displaying 1-22 of 22 articles from this issue
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Regular Articles
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Sevgi Tatar Ulu, Zeynep AydogmusArticle type: Regular Article
2008 Volume 56 Issue 12 Pages 1635-1638
Published: December 01, 2008
Released on J-STAGE: December 01, 2008
JOURNAL FREE ACCESSA new rapid and sensitive procedure assay is proposed for the spectrophotometric determination of tianeptine. The developed method involves formation of colored chloroform extractable ion-pair complexes of tianeptine with bromophenol blue (BPB), bromocresol green (BCG), bromothymol blue (BTB) and methyl orange (MO) in acidic medium. Beer's law is obeyed in the concentration ranges 3.0—12.0, 4.0—16.0, 4.0—14.0 and 2.0—10.0 μg ml−1 with BPB, BCG, BTB and MO, respectively. The detection limit of tianeptine was found to be 1.8 μg ml−1 for BPB, 2.0 for BCG, 2.0 μg ml−1 for BTB and 1.0 μg ml−1 for MO. Validation of the method was performed in terms of linearity, limit of detection (LOD), quantification (LOQ), accuracy and precision. Common excipients used as additives in pharmaceutical preparations do not interfere in the proposed method. The proposed method has been applied to determination of the examined drugs in pharmaceutical formulations and the results demonstrated that the method is equally accurate, precise, and reproducible as the official method. The t-test showed no significant difference at 95% confidence level.View full abstractDownload PDF (120K) -
Farnaz Jabbaribar, Alireza Mortazavi, Reza Jalali-Milani, Abolghasem J ...Article type: Regular Article
2008 Volume 56 Issue 12 Pages 1639-1644
Published: December 01, 2008
Released on J-STAGE: December 01, 2008
JOURNAL FREE ACCESSA simple and rapid micellar electrokinetic chromatography (MEKC) method was developed for the analysis of an antiviral drug, oseltamivir, and its hydrolyzed product in Tamiflu® capsules. Background electrolytes consisted of boric acid 10 mM, pH 10, and sodium dodecyl sulphate (SDS) 40 mM. The limit of detection (LOD) and limit of quantification (LOQ) of oseltamivir were 1.7 and 8.0 μg/ml, respectively. MEKC sweeping in a high electroosmotic flow environment for neutral analytes was also utilized to improve the sensitivity of the assay. In MEKC-sweeping mode, a buffer comprising boric acid 30 mM, pH 10, and SDS 50 mM was used. A 17-fold increase in detection sensitivity was achieved with the MEKC-sweeping method compared with the MEKC mode. Unlike in MEKC, the LOD and LOQ for oseltamivir were 0.1 and 0.3 μg/ml, respectively, using the MEKC-sweeping method. Both methods were successful in determining oseltamivir concentration in its capsule formulation, and the MEKC-sweeping method was capable of determination of the drug at lower concentrations. The hydrolyzed product of oseltamivir (oseltamivir carboxylate) was also detected using the MEKC method. Our observations revealed that the prodrug could be hydrolyzed to the active compound at alkaline pH within ca. 60 min.View full abstractDownload PDF (118K) -
Xinxin Zhang, Weisan Pan, Li Gan, Chunliu Zhu, Yong Gan, Shufang NieArticle type: Regular Article
2008 Volume 56 Issue 12 Pages 1645-1650
Published: December 01, 2008
Released on J-STAGE: December 01, 2008
JOURNAL FREE ACCESSNanostructured lipid carriers (NLC) are based on mixture of solid lipids with spatially incompatible liquid lipids, which offer advantages of improving drug loading capacity and release properties. In the present study, hydroxycamptothecin (HCPT) loaded polyethylene glycol (PEG) modified NLC (PEG-NLC) was prepared by high pressure homogenize and spray drying method. PEG-NLC showed spherical particle with smooth surface in scanning electron microscopic (SEM) analysis. The crystallinity of lipid matrix within PEG-NLC was evaluated by powder X-ray diffraction and differential scanning calorimetry (DSC). The less ordered crystals or amorphous state of matrix were found in nanoparticles. A small, homogeneous particle size and high drug loading with fine entrapment efficiency of HCPT was obtained in PEG-NLC system. HCPT releasing from PEG-NLC showed a sustained release trend, and no significantly difference was found between two release curves of PEG-NLC before or after spray drying. After storage for 6 months, PEG-NLC powder after spray drying showed no significantly changes in particle size, drug loading and entrapment efficiency, crystal form and in vitro release. PEG modification statistically decreased the phagocytosis of NLC by RAW 264.7 cells, and spray drying process did not influence the cellular uptake of PEG-NLC. These results suggest that PEG-NLC prepared by spray drying is a stable and high-performance delivery system for HCPT.View full abstractDownload PDF (864K) -
Amr Mohamed BeltagiArticle type: Regular Article
2008 Volume 56 Issue 12 Pages 1651-1657
Published: December 01, 2008
Released on J-STAGE: December 01, 2008
JOURNAL FREE ACCESSAn easy, rapid and selective adsorptive stripping voltammetry (AdSV) method for the determination of vincamine in its formulation and human serum was developed and validated. It was based on the oxidation of the drug onto a Nujol-based carbon paste electrode. The stripping step was carried out by using a square-wave (SW) potential-time voltammetric excitation signal. The optimal experimental variables as well as accumulation parameters were investigated as; frequency f=120 Hz, scan increment ΔEi=10 mV, pulse-amplitude ΔEa=25 mV and an accumulation potential Eacc of 0.0 V using a Britton–Robinson (B-R) universal buffer of pH 5 as a supporting electrolyte. After validation of the described method, it was applied for determination of vincamine in its formulation and human serum. Mean recovery of 100.41±0.74 (n=5) was achieved for assay of vincamine in Oxybral® capsules. Limits of detection and quantitation of 6.0×10−9 M (2.20 ng ml−1) and 2×10−8 M (7.33 ng ml−1) vincamine were achieved in human serum with a mean recovery of 99.5±1.79%, without prior extraction of the drug. No interferences were observed in formulation and/or human serum. Due to high sensitivity and specificity of the developed method, it was successfully applied for evaluating some pharmacokinetic parameters of two healthy volunteers after administration of a single oral Oxybral® capsule.View full abstractDownload PDF (167K) -
Paruvathanahalli Siddalingam Rajinikanth, Lakshmi Narayanan Karunagara ...Article type: Regular Article
2008 Volume 56 Issue 12 Pages 1658-1664
Published: December 01, 2008
Released on J-STAGE: December 01, 2008
JOURNAL FREE ACCESSThe objective of the study was to develop a stomach-specific drug delivery system for controlled release of clarithromycin for eradication of Helicobacter pylori (H. pylori). Floating-bioadhesive microspheres of clarithromycin (FBMC) were prepared by emulsification-solvent evaporation method using ethylcellulose as matrix polymer and Carbopol 934P as mucoadhesive polymer. The prepared microspheres were subjected to evaluation for particle size, incorporation efficiency, in vitro buoyancy, in vitro mucoadhesion and in vitro drug release characteristics. The prepared microspheres showed a strong mucoadhesive property with good buoyancy. The formulation variables like polymer concentration and drug concentration influenced the in vitro drug release significantly in simulated gastric fluid (pH. 2.0). The in vivo H. pylori clearance efficiency of prepared FBMC in reference to clarithromycin suspension following repeated oral administration to H. pylori infected Mongolian gerbils was examined by polymerase chain reaction (PCR) technique and by a microbial culture method. The FBMC showed a significant anti-H. pylori effect in the in vivo gerbil model. It was also noted that the required amount of clarithromycin for eradication of H. pylori was significantly less in FBMC than from corresponding clarithromycin suspension. The results further substantiated that FBMC improved the gastric stability of clarithromycin (due to entrapment within the microsphere) and eradicated H. pylori from the gastrointestinal tract more effectively than clarithromycin suspension because of the prolonged gastrointestinal residence time of the formulation.View full abstractDownload PDF (834K) -
Ailin Liu, Wei Chen, Liying Huang, Xinhua LinArticle type: Regular Article
2008 Volume 56 Issue 12 Pages 1665-1669
Published: December 01, 2008
Released on J-STAGE: December 01, 2008
JOURNAL FREE ACCESSA novel uric acid electrochemical sensor was fabricated by electropolymerization on glassy carbon electrode (GCE) with 4-(2-pyridylazo)-resorcinol (PAR) and its electrochemical property was investigated through cyclic voltammetry. The effect of film thickness on the oxidation response was also studied by electropolymerized scan times. The voltammetric behavior of uric acid (UA) was studied with the poly PAR modified GCE. The modified GCE was used to electrochemically detect the individual of UA and the mixture of UA and ascorbic acid (AA) by cyclic voltammetry (CV) or differential pulse voltammetry (DPV) method. For the ternary mixture containing UA and AA, the two compounds can well be separated from each other at a scan rate of 100 mV s−1 with a potential difference of 345 mV in DPV between UA and AA. The peak currents of UA oxidation increase linearly with the concentration in ranges of 1.0×10−8—5.0×10−5 mol l−1, and the detection limits (S/N=3) was 1.0×10−9 mol l−1. This method was successfully applied to the determination of uric acid in human urine samples.View full abstractDownload PDF (171K) -
Yong-Qin Yin, Xue-Feng Huang, Ling-Yi Kong, Masatake NiwaArticle type: Regular Article
2008 Volume 56 Issue 12 Pages 1670-1674
Published: December 01, 2008
Released on J-STAGE: December 01, 2008
JOURNAL FREE ACCESSThree new pentasaccharide resin glycosides, batatosides III—V (1—3), were isolated from the roots of Sweet potato (Ipomoea batatas). Saponification of the crude resin glycoside mixture yielded substituents and simonic acid B. The structures of the isolated compounds (1—3) were established through spectroscopic analyses, including high field NMR spectroscopy and HR-ESI-MS, and chemical correlation. The major characteristics of 3 are the presence of three different substituents, especially the substituent of cinnamic acid was seldom. The monosaccharides of 1—3 were proved by GC-MS and the absolute configuration of aglycone was further established as S by Mosher's method with R-methyloxyphenylacetic acid (MPA) and S-MPA.View full abstractDownload PDF (155K) -
Halise Inci Gul, Kadir Ozden Yerdelen, Umashankar Das, Mustafa Gul, Bu ...Article type: Regular Article
2008 Volume 56 Issue 12 Pages 1675-1681
Published: December 01, 2008
Released on J-STAGE: December 01, 2008
JOURNAL FREE ACCESSThe reaction of various 4′-hydroxychalcones (1a—e) with paraformaldehyde and dibenzylamine led to the formation of a novel series of 4′-hydroxy-3′-dibenzylaminomethyl chalcones (7a—e) instead of 4′-hydroxy-3′,5′-bis-(dibenzylaminomethyl)chalcones 4. In order to rationalise the formation of monoadduct 7, energy minimized model structures of 4a and 7a were compared. The in vitro cytotoxic activities of 7a—e were tested against PC-3 cell lines for the first time in this study and compared with the precursor 4′-hydroxychalcones (1a—e). Except for compound 7a (IC50: 19.85 μM), insertion of dibenzylaminomethyl function into 4′-hydroxychalcones resulted in complete loss of cytotoxic activity. The results suggested that it is not only the pKa but also the shape and size of the amine that is critical in governing the cytotoxic activity.View full abstractDownload PDF (196K) -
Kaname Hashizaki, Nao Tamaki, Hiroyuki Taguchi, Yoshihiro Saito, Koji ...Article type: Regular Article
2008 Volume 56 Issue 12 Pages 1682-1686
Published: December 01, 2008
Released on J-STAGE: December 01, 2008
JOURNAL FREE ACCESSIn the present study, we examine a worm-like micelle consisting of a nonionic surfactant system of polyoxyethylene phytosterol (PhyEOm)/glycerin fatty acid monoester (GFA-Cn)/Water (m=10, 20, 30; n=8, 10, 12) using rheological measurements looking towards potential application of the system as a gel base. Phase diagrams in the dilute region of the PhyEOm/GFA-Cn/Water systems show the formation of worm-like micelles in some of the surfactant combinations. It is thought that the worm-like micelles form with the GFA-Cn solubilized in the palisade layer of a spherical or rod-like micelle consisting of PhyEOm, resulting in a decrease in the interfacial curvature of the molecular assembly. The rheological properties of micellar solutions were examined while changing the ratio of GFA-Cn (R) with the total concentration of the surfactants (wt%) fixed. Steady-flow viscosity measurements in the region of worm-like micelle formation showed Newtonian flow in the low shear rate region and non-Newtonian flow at higher shear rates. This result shows that the network structure of worm-like micelles does not break in the low shear rate region, but does break in the high shear rate region. The zero-shear viscosity (η0) was calculated from the steady-flow viscosity curve and was found to change dramatically with changing R value, increasing to a value 10000 times that of other values at the maximum. Thus, there is an optimal composition of surfactants which leads to the greatest entanglement of the worm-like micelles. To consider the change in η0 in detail, dynamic viscoelasticity measurements were carried out. Consequently, the viscoelastic behavior of the worm-like micelles was found to be similar to the Maxwell model, which represents the most basic model for a viscoelastic body, and it was shown that this worm-like micelle had a single relaxation time. Moreover, it was found that the change in η0 of a worm-like micelle was influenced by its mechanical strength.View full abstractDownload PDF (306K) -
Ubonta Sommart, Vatcharin Rukachaisirikul, Yaowapa Sukpondma, Souwalak ...Article type: Regular Article
2008 Volume 56 Issue 12 Pages 1687-1690
Published: December 01, 2008
Released on J-STAGE: December 01, 2008
JOURNAL FREE ACCESSThree new hydronaphthalenone derivatives (1—3) and one new dihydroramulosin derivative (4), were isolated from the endophytic fungus PSU-N24 together with eight known compounds. Their structures were elucidated by spectroscopic methods. Griseofulvin (9) displayed strong antifungal activity against Microsporum gypseum SH-MU-4 with a minimum inhibitory concentration (MIC) value of 2 μg/ml while all metabolites exhibited very weak antibacterial activity (MIC value≥128 μg/ml) against Staphylococcus aureus, both standard and methicillin-resistant strains. 3-(2-Hydroxypropyl)benzene-1,2-diol (10) showed moderate antimalarial activity against Plasmodiun falciparum with an IC50 value of 6.68 μg/ml. For antimycobacterial activity against Mycobacterium tuberculosis, compound 3 gave the best activity with the MIC value of 12.50 μg/ml.View full abstractDownload PDF (113K) -
Kimihiko Sato, Keito Sugawara, Hirono Takeuchi, Hyun-Sun Park, Toshiyu ...Article type: Regular Article
2008 Volume 56 Issue 12 Pages 1691-1697
Published: December 01, 2008
Released on J-STAGE: December 01, 2008
JOURNAL FREE ACCESSTwo new sempervirol type diterpenes, inumakiols A, B, and six new totarol type diterpenes, inumakiols C—H, were isolated from a methanolic extract of bark of Podocarpus macrophyllus (Podocarpaceae), along with one known abietane, two known totarol type diterpenes, and one known totarol type diterpene dimer. The structures of the new compounds were elucidated by the spectroscopic methods. Some of them possessed antibacterial activity against oral pathogenic microorganisms with minimum inhibitory concentration (MIC) values ranging from 3.1 to 25 ppm.View full abstractDownload PDF (387K) -
Hideko Maeda, Takeshi Chiba, Mitsutomo Tsuhako, Hirokazu NakayamaArticle type: Regular Article
2008 Volume 56 Issue 12 Pages 1698-1703
Published: December 01, 2008
Released on J-STAGE: December 01, 2008
JOURNAL FREE ACCESSThe phosphorylation of nucleosides (adenosine, guanosine, cytidine, and uridine) and nucleotides (adenosine 5′-monophosphate, guanosine 5′-monophosphate, cytidine 5′-monophosphate and uridine 5′-monophosphate) has been achieved using inorganic monoimido-cyclo-triphosphate (MCTP, Na3P3O8NH) in aqueous solution. In this reaction, the 2′-OH or 3′-OH group of the β-D-ribofuranose unit was phosphorylated and the total yield was more than 30% and 14%, respectively. The main products were 2′-diphosphoramidophosphononucleoside and 2′-diphosphoramidophosphononucleoside 5′-monophosphate.View full abstractDownload PDF (244K) -
Seikou Nakamura, Yoshie Okazaki, Kiyofumi Ninomiya, Toshio Morikawa, H ...Article type: Regular Article
2008 Volume 56 Issue 12 Pages 1704-1709
Published: December 01, 2008
Released on J-STAGE: December 01, 2008
JOURNAL FREE ACCESSThe 80% aqueous acetone extract from the flowers of Hedychium coronarium was found to show a protective effect on D-galactosamine-induced cytotoxicity in primary cultured mouse hepatocytes. On the other hand, two new labdane-type diterpene glycosides, coronalactosides I (1) and II (2), and a new labdane-type trinorditerpene, coronadiene (3), were isolated together with 8 known compounds from the extracts, which were obtained with chloroform and 80% aqueous acetone from the flowers of H. coronarium. The structures of new constituents were elucidated on the basis of chemical and physicochemical evidence. In addition, the principal constituents, coronaririn C and 15-hydroxylabda-8(17),11,13-trien-16,15-olide, displayed hepatoprotective effects, which were stronger than that of the hepatoprotective agent, silybin.View full abstractDownload PDF (189K) -
Fengming Xu, Seikou Nakamura, Yang Qu, Hisashi Matsuda, Yutana Pongpir ...Article type: Regular Article
2008 Volume 56 Issue 12 Pages 1710-1716
Published: December 01, 2008
Released on J-STAGE: December 01, 2008
JOURNAL FREE ACCESSFrom the methanolic extract of the rhizomes of Curcuma comosa cultivated in Thailand, six new sesquiterpenes, (+)- and (−)-comosols (1, 2), comosones I (3), II (4), and III (5), and dimethoxycurcumenone (6), were isolated. Their structures were elucidated on the basis of chemical and physicochemical evidence.View full abstractDownload PDF (257K)
Notes
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Sherine Nabil Khattab, Adnan Ahmed Bekhit, Ayman El-Faham, Abdel Monei ...Article type: Notes
2008 Volume 56 Issue 12 Pages 1717-1721
Published: December 01, 2008
Released on J-STAGE: December 01, 2008
JOURNAL FREE ACCESSA series of new pyridazinylacetic acid derivatives were synthesized and have been investigated for their ability to inhibit the activity of the A and B isoforms of monoamine oxidase (MAO). All compounds were found to be more selective to the MAO-A isoform with compound 5d having the highest SI values. Computational study performed with a docking technique indicated the potential of these compounds in pyridazine-based MAO-A inhibitor drug development.View full abstractDownload PDF (318K) -
Ren-Bo An, Gil-Saeng Jeong, Youn-Chul KimArticle type: Notes
2008 Volume 56 Issue 12 Pages 1722-1724
Published: December 01, 2008
Released on J-STAGE: December 01, 2008
JOURNAL FREE ACCESSTwo flavonoids, 4,2′,5′-trihydroxy-4′-methoxychalcone (1) and (2S)-6,7,4′-trihydroxyflavan (2), along with fourteen known flavonoids and two other known arylbenzofurans were isolated from the heartwood of Dalbergia odorifera. The structure of compounds 1 and 2 were established by spectroscopic (NMR and MS) analyses. Of the isolates, eight compounds (1, 4, 7, 10, 12, 14, 15, 17) were found to have potent protective effect on glutamate-induced oxidative injury in HT22 cells.View full abstractDownload PDF (98K) -
Byung-Sun Min, Cao Van Thu, Nguyen Tien Dat, Nguyen Hai Dang, Han-Su J ...Article type: Notes
2008 Volume 56 Issue 12 Pages 1725-1728
Published: December 01, 2008
Released on J-STAGE: December 01, 2008
JOURNAL FREE ACCESSFour new flavonoids, 3′-formyl-4′,6′,4-trihydroxy-2′-methoxy-5′-methylchalcone (1), 3′-formyl-6′,4-dihydroxy-2′-methoxy-5′-methylchalcone 4′-O-β-D-glucopyranoside (2), (2S)-8-formyl-6-methylnaringenin (3), and (2S)-8-formyl-6-methylnaringenin 7-O-β-D-glucopyranoside (4) were isolated from the buds of Cleistocalyx operculatus (Myrtaceae). The structures of the new metabolites (1—4) were determined on the basic of spectroscopic analyses including 2 dimensional NMR. Compounds 1 and 3 exhibited 1,1-diphenyl-2-picrylhydrazyl radical scavenging activity with IC50 values of 22.8 and 27.1 μM, respectively.View full abstractDownload PDF (97K) -
Shuang Liang, Jian Tang, Yun-Heng Shen, Hui-Zi Jin, Jun-Mian Tian, Zhi ...Article type: Notes
2008 Volume 56 Issue 12 Pages 1729-1731
Published: December 01, 2008
Released on J-STAGE: December 01, 2008
JOURNAL FREE ACCESSBioassay-directed fractionation led to the isolation of two new biflavonoids and 13 known biflavonoids from a sample of the dried stem barks of Daphne feddei. The structures of compounds 1 and 2 were elucidated as 2″-methoxy-daphnodorin C (1) and 2″-methoxy-2-epi-daphnodorin C (2) on the basis of detailed spectroscopic analysis and X-ray crystallography. All 15 biflavonoids were tested for inhibitory activities against lipopolysaccharide (LPS)-induced nitric oxide (NO) production in RAW 264.7 macrophages. Compounds 1, 2, 8, 10, 14 and 15 showed varying degrees of inhibitory activities against the production of NO in tested concentration of 25, 50, 75 and 100 μg/ml.View full abstractDownload PDF (184K) -
Cherkupally Sanjeeva Reddy, Mekala RaghuArticle type: Notes
2008 Volume 56 Issue 12 Pages 1732-1734
Published: December 01, 2008
Released on J-STAGE: December 01, 2008
JOURNAL FREE ACCESSThe synthesis of novel 6,6′-methylene-bis-[3-(2-anilinoacetyl)-4-hydroxycoumarin] derivatives 6a—f was achieved in excellent yields from 6,6′-methylene-bis-[3-(2-bromoacetyl)-4-hydroxycoumarin] 5 and various arylamines. 5,5′-Methylene-bis-ethylsalicylate 3 was obtained by the esterfication of 5,5′-methylene-bis-salicylic acid 2 with ethanol, which was in turn obtained from salicylic acid 1 and formaldehyde. Cyclocondensation of 3 with ethyl acetoacetate resulted in 6,6′-methylene-bis-[3-acetyl-4-hydroxycoumarin] 4, which on selective α-bromination with molecular bromine in the presence of montmorillonite K10–AlCl3 catalyst, in chloroform–ethyl acetate binary solvent mixture at room temperature, afforded the compound 5 in excellent yield. All the newly synthesized compounds were characterized by their spectral data.View full abstractDownload PDF (103K) -
Kazuhito Hioki, Yumiko Takechi, Noriyo Kimura, Hiroyuki Tanaka, Muneta ...Article type: Notes
2008 Volume 56 Issue 12 Pages 1735-1737
Published: December 01, 2008
Released on J-STAGE: December 01, 2008
JOURNAL FREE ACCESSSimple one-pot methods for preparation of 2-oxazolines have been developed using 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride (DMT-MM). Treatment of a mixture of carboxylic acids and 2-haloethylammonium salts with DMT-MM in methanol followed by refluxing in the presence of KOH gives oxazolines.View full abstractDownload PDF (110K) -
Kouji Kuramochi, Kensuke Ohnishi, Satoshi Fujieda, Mitsuhiro Nakajima, ...Article type: Notes
2008 Volume 56 Issue 12 Pages 1738-1743
Published: December 01, 2008
Released on J-STAGE: December 01, 2008
JOURNAL FREE ACCESSWe synthesized a series of neoechinulin A derivatives and examined the structure–activity relationships in terms of their anti-nitration and anti-oxidant activities as well as their cytoprotective activity against peroxynitrite from SIN-1 (3-(4-morpholinyl)sydnonimine hydrochloride) using PC12 cells. Our results showed that the C-8/C-9 double bond, which constitutes a conjugate system with indole and diketopiperazine moieties of neoechinulin A is essential for anti-nitration and anti-oxidant activities as well as protection against SIN-1 cytotoxicity. The presence of an intact diketopiperazine moiety is an additional requirement for anti-nitration activity but not for the cytoprotective action. Our results suggest that the antioxidant activity or electrophilic nature of the C-8 carbon, both of which are afforded by the C-8/C-9 double bond, may play a role in the cytoprotective properties of this alkaloid.View full abstractDownload PDF (440K)
Errata
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2008 Volume 56 Issue 12 Pages 1744
Published: 2008
Released on J-STAGE: December 01, 2008
JOURNAL FREE ACCESSDownload PDF (11K)
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