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Cimicifuga racemosa and its triterpene-saponins prevent the Metabolic Syndrome and deterioration of cartilage in the knee joint of ovariectomized rats by similar mechanisms.

ARTICLE INFO

Keywords:

Ovariectomized rats

Metabolic Syndrome

Fat tissue

Cholesterol

Joint cartilage

Cimicifuga racemosa

ABSTRACT

Purpose: An unphysiologic accumulation of fat cells in many parts of the body including abdomen and joints results in increased production of pro-inflammatory cytokines which have adverse effects on serum lipids, glucose and on joint cartilage. The special extract of Cimicifuga racemosa CR BNO 1055 was shown to reduce the size of the abdominal fat depot. It was therefore tempting to test whether this extract, its saponin and its unpolar and polar fractions S-and R-fraction respectively (no quotation) also reduce fat depots and fat cell accumulation in a fat depot located in the lower hind leg (called paratibial fat depot = PFD), in joint fat pads (in the knee joint this is called Hoffa's fat pad) that occur in response to ovariectomy and whether this was accompanied by reduced serum lipids, glucose and improved cartilage features in the knee joint.

Methods: Rats (n= 10/group) were ovariectomized (ovx) and fed with CR BNO 1055, S-or R-fraction con-taining food (average intake 8.2, or 2.05 or 7.07 mg/day/animal) for 4 weeks. Ovx rats kept under no additive-containing food served as controls. The sizes of the PFD, of Hoffa's fat pad and of the cartilage thickness of the knee joints were determined by quantitative computer tomography and histomorpho-metrically. In the serum cholesterol, leptin and glucose levels were measured.

Results: High load with fat tissue in the PFD and in the knee joints was present in the ovx rats. Treatment with CR BNO 1055 and its S-fraction reduced fat load of both, Hoffa's fat pad and of the PFD significantly and this resulted in reduced body weight which was significant under CR BNO 1055. Fat load in the PFD correlated significantly with the height of serum leptin and cholesterol. The fat load in the knee joint correlated inversely with the size of knee cartilage tissue.

Conclusions: High fat load of the body increases following ovx and this causes increased serum leptin, cholesterol and glucose levels. Following ovx the size of Hoffa's fat pad increases also significantly and this has adverse effects on knee cartilage tissue. Therefore, increased fat tissue in joints appears to belong to the Metabolic Syndrome. This effect can be largely prevented by CR BNO 1005 and its S-but not by its R-fraction. Hence, the saponins in CR BNO 1055 may be useful in preventing the Metabolic Syndrome and osteoarthritis.

[c] 2012 Elsevier GmbH. All rights reserved.

Introduction

It is now well accepted that two types of obesities do exist. The pear or gynoid type of fat distribution stands for accumulation of fat tissue in the hip and thigh region. In case of the apple or android type of obesity, fat accumulates in the abdominal cavity. This visceral fat has negative features; it secretes pro-inflammatory cytokines and adipokines such as TNF[alpha], IL6, adiponectin, leptin and others (de Ferranti and Mozaffarian 2008; Klein-Wieringa et al. 2011; Rai and Sandell 2011) which are responsible for the development of hypercholesterolemia, arteriosclerosis, heart attacks and type 11 diabetes. These diseases are nowadays summarized as the Metabolic Syndrome (Ford et al. 2002; Watts and Karpe 2011).

Rheumatoid osteoarthritis is a common disease which is due to autoimmune inflammatory processes (Hazes and Luime 2011). Another type of arthritis is the formerly called arthrosis which occurs primarily in hip and knee joints. Since it develops primarily in overweight persons it was assumed that the overweight is the exclusive reason for the deterioration of cartilage in the knee (Bliddal et al. 2011). Lately evidence accumulates that fat pads, located in joints, also pay a role in the generation of arthrosis (Gandhi et al. 2011; Klein-Wieringa et al. 2011; Rai and Sandell 2011). These fat pads, particularly, Hoffa's fat pad in the knee joint are often enlarged in overweight persons (Hazes and Luime 2011). The adipocytes in joint fat pads share the negative features of visceral fat cells by secreting pro-inflammatory adipo- and cytokines and cause, therefore, local inflammatory processes in the joints. The secreted pro-inflammatory cytokines inhibit maturation of chondrocytes and cause the increased formation of matrix met-alloproteinases which destroy the infrastructure of joint cartilage tissue (Rai and Sandell 2011 ). In the knee and hip joints these effects are augmented by the overweight of the obese people. Hence, arthrosis is not only a degenerative disease due to mechanical compression of cartilage tissue, but an inflammatory component is at least as important in the development and progression of this disease. Because of these inflammatory processes which also occur in the bone, arthrosis is now called osteoarthritis which in many patients is an integral part of the Metabolic Syndrome.

Ovariectomized (ovx) rats become obese and develop a Metabolic Syndrome including hyperglycemia (Chen and Heiman 2001; Gorres et al. 2011; Seidlova-Wuttke et al. 2003; Zoth et al. 2010). Furthermore, we demonstrated recently that ovx has adverse effects on joint cartilage tissue by thinning of the cartilage layer. This is suggestive to us that the ovx rat is a good model for the study of the Metabolic Syndrome and of osteoarthritis (Kapur et al. 2010).

In several reports we gave evidence that the special extract of Cimicifuga racemosa (CR) BNO 1055 prevents visceral obesity in ovx rats (Seidlova-Wuttke et al. 2003). Therefore, it was tempting to study the possibility that this extract can prevent ovx induced hyperlipidemia and hyperglycemia. Furthermore we tested whether CR-BNO 1055 resulted in less articular fat accumulation in the knee joint and whether this correlated with the size of the cartilage tissue in this joint.

In addition to the special extract CR BNO 1055 we also tested the saponin fraction (5-fraction) and a fraction containing the more polar substances of this extract (R-fraction). Thus, we tried to solve the question which of these fractions was responsible for the obesity preventive effects and the possibly accompanying reduction of hyperlipidemia and whether the fraction that prevented development of obesity was also effective to ameliorate an increased size of Hoffa's fat pad and thereby the adverse effects of ovx on cartilage tissue in the knee joint.

Materials and methods

Allowance to perform the animal experiments was obtained from the district authorities of Braunschweig, Germany (permission no. Az. 33.425002-082/06). Three-months-old female SD-rats (Winkelmann, Borken, Germany) were adjusted to the animal facilities of the Gottingen University Hospital and kept in groups of six in Makrolon cages (type 4) under a 12-h light, 12-h dark cycle at room temperature of 24-26 C and relative humidity of 50-55% with food and water ad libitum. After 4 weeks adjustment to the animal facilities, the rats weighing 270 [+ or -] 4.4 g were ovx and groups randomized according to the bodyweights (BW) such that each group had identical BW.They were fed with soy-free food (V 1355 R-Z, 10 mm, poor phytoestrogens, ssniff, Soest, Germany) in order to eliminate exposure to soy-derived estrogenic compounds found in regular rodent show. Isocaloric protein supplementation was secured by added potato proteins. The test substances were the special CR extract CR BNO 1055 and the thereof fractionated lipophilic and hydrophilic compounds. All test extracts were produced by Bionorica SE (Neumarkt, Germany) as follows:

Plant material

As plant material the special extract from Cimicifuga racemosa CR BNO 1055 (Bionorica SE, Neumarkt, Germany) was used, of which the preparation was described previously (kapur et al. 2010). This extract stems from rhizomes of Cimicifuga racemosa which was grown, harvested and extracted under rigidly controlled conditions.

Chemical and reagents

For the fractionation process we used dichloromethane (Emsure[R], Merck, Darmstadt, Germany). Purified water for the separation process and as solvent for the HPLC system was produced by the Milli-Q Water Purification System (Millipore GmbH, Schwalbach, Germany). Analytical grade ethyl acetate and formic acid for TLC analysis were purchased from VWR International GmbH (Darmstadt, Germany). The eluents for the chromatographic analysis, acetonitrile and methanol, were gradient grade (Merck, Darmstadt, Germany). Pure formic acid 99-100% as additive for the mobile phase was purchased from VWR.

Fractionation process

The separation of the triterpeneglycosides from the hydrophilic components of the special extract BNO 1055 was obtained via liquid-liquid-extraction (LLE). The crude extract was partially dissolved in water and sonicated for 15 min. For improved separation of the phenylpropanoids the pH-value of the suspension was adjusted to 8.5 and dichloromethane was added and mixed for 1 h at 33 C. The mixture was transferred into a separatory funnel to separate the lipophilic from the hydrophilic phase. After partition of the dichloromethane phase the LLE was repeated.

In order to obtain a solvent-free dichloromethane fraction, the pooled fractions were evaporated by using a rotary evaporator (Buchi Labortechnik GmbH, Essen, Germany) and lyophilized. The quality of separation of the obtained fractions was analyzed by TLC, HPLC-ELSD and HPLC-MS.

Sample preparation

For TLC and HPLC-ELSD analysis the native dry extract and the dried fractions were dissolved in 100% methanol (10 g/l) and sonicated for 15 min at room temperature. For HPLC-MS samples were prepared similarly with a final concentration of 2.5 g/L Prior to analysis all samples were filtered through a Chromafil[R] PET-45/25 filter (Macherey-Nagel GmbH & Co. KG, Duren, Germany).

Instrumentation and chromatographic conditions

TLC analysis was performed with Automatic TLC Sampler 4 (Camag, Muttenz, Switzerland) using winCATS 1.4.6 software (Camag, Muttenz, Switzerland). Separation was achieved with a HPTLC silica gel 60 F254 20 cm x 10 cm plate (Merck, Darmstadt, Germany). Mobile phase consisted of ethylacetate:formic acid:water (95:5:5). The application volume of each sample was 104 sprayed in 15 mm bands. Detection of the zones was achieved by immerse in 10% sulfuric acid and following heating for 5 min at 105 C. Visualization of the fluorescence at 366 nm was assessed by Desaga ProViDoc[R] Version 5.4. (Sarstedt, Nurnbrecht, Germany) equipped with a Canon Powershot G9 camera.

HPLC-ELSD analysis was performed with an Agilent 1200 Series chromatography system (Agilent Technologies Deutschland, Boblingen, Germany) equipped with a binary pump, degasser, autosampler, column thermostat, diode array detector and an evaporative light scattering detector (ELSD). A Synergi MAX-RP column 150 mm x 4.60 mm 4 p.m (Phenomenex, Aschaffenburg, Germany) was used as stationary phase and was run at a temperature of 20 C. The mobile phase comprised of 0.1% formic acid (solvent A) and 100% acetonitrile (solvent B). Starting condition was 20% of solvent B (80% solvent A) at a flow rate of 1 ml/min. The gradient started with an increase to 30% B in 1 min, followed by holding 30% B for 4 min, afterwards an increase to 607'1) B in 13 min and finally in 0.1 min to 100% B. Each run was followed by a 5 min wash with 100% of solvent B and an equilibration for 5 min at starting conditions. The injecting volume amounted to 10 [micro]l for each sample. For determination a DAD (330 nm) and a connected ELSD were used. The parameters for ELS detection were set up to 40 C nebulizer temperature, at gain 10 and the nebulizer nitrogen flow adjusted to 3.2 bar (Fig. 1).

HPLC-MS analysis was performed with an Agilent 1200 Series Chromatography system equipped with a quaternary pump, degasser, autosampler, column thermostat and a diode array detector (Agilent Technologies Deutschland GmbH, Boblingen, Germany). The mass spectrometric analysis were performed by using an Agilent single quadrupole 6130 Series (G6130A, Agilent Technologies Deutschland GmbH, Boblingen, Germany) invested with an APCI source. Separation was achieved on a Prodigy 5u ODS (3) 100A 250 mm x 4.60 mm 5 [micro]m column (Phenomenex, Aschaffenburg, Germany) at a flow rate of 1 ml/min at 40[degrees]C. The mobile phase consisted of water with 0.1% formic acid (solvent A) and methanol 100% (solvent B) with the following gradient elution: start condition 3% B (97% solvent A), increase in 18 min to 23% B, within 7 min to 45% B, within 15 min to 60% B and finally an increase to 100% B in 35 min. A 5 min wash cycle and an equilibration time of 5 min followed this gradient. The injection volume was set up to 10 [micro]l The effluent was monitored with DAD (330 nm) and MS-detector, which operated in a positive/negative-switching full scan mode with a mass range from m/z 100-800. The gas temperature was set to 325 C by a corona potential of 4.0 [micro]A (positive), 20 pa; (negative) and a capillary voltage of 4000 V. The nitrogen gas flow was adjusted to 5.01/min (Fig. 2).

The original extract CR BNO 1055 and the thereof produced S-and R-fraction were mixed with the above described food. The animal groups, their daily food and extract intake and the weight gain from the beginning until the end of the 4 week lasting experimental period are detailed in Table 1. At the end of this period animals were sacrificed under [CO.sub.2] anesthesia, blood was collected from the trunk and a specimen consisting of the lower part of the femur, the knee joint and the upper part of the tibia was collected from each animal.

Table 1

Food and extract intake of different treatment groups.

Group              Number of  Food intake  Intake of        [DELTA] BW
                 animals (n)      (g/day/  test extracts  (g) increase
                                  animal)       (mg/day/  from initial
                                                 animal)            BW

Co (ovx)                 10            17              0         94.48
ovx CR BNO 1055          10         16.45           8.22         74.41
ovx S-fraction           10         17.42           2.05         87.47
ovx R-fracrion           10         18.49           7.07         81.94

* P<O.05 vs Co (ovx).


Quantitative computer tomography (qCT)

Prior to ovx and a day prior to sacrifice of the animals the upper metaphyses of the tibiae were subjected to cri utilizing the Stratec x CT 5.40 equipment (Stratec Inc., Pforzheim, Germany). In short, under isoflurane anesthesia the scanner was positioned at the level of the epiphyseal growth plate and this was the reference line. QCT measures were performed 3.75 and 4.25 mm distal of this reference line. Densities are calculated as means of the 1st and 2nd CT plane and are given in mg/[cm.sup.3]. Areas with densities below 40 mg/[cm.sup.3] are considered to be fat tissue. This allowed determination of a fat depot laying in the lower hind leg which we named paratibial fat depot (PFD) and of which we showed previously that it is large in ovx and much smaller in intact or ovx-E2 treated animals (Seidlova-Wuttke et al. 2010). Hence, this fat depot shared the properties of the visceral fat tissue.

Histological evaluation of the knee joint

At the end of the experimental period a variety of organs were collected from each animal, among others, specimens of the lower femur/knee joint/upper tibia.

The cleaned bone/joint specimens were embedded in Epoxy and allowed to harden for a period of 4-6 weeks. After hardening longitudinal cuts of 5 [in thickness were prepared and stained according to Goldner. In mid-sectional cuts (10/animal) (Fig. 3) the surface of Hoffa's fat pad was perimetrically determined and the thickness of the cartilage layer of the tibial part of the knee joint was quantified.

Serum analysis

Serum leptin levels were measured by a commercially available radioimmunoassay (DSL Inc., Webster, TX, USA). Serum glucose and cholesterol were quantified using a Hitachi 911 analyzer (Roche, Mannheim, Germany).

Statistical analysis

The histological parameters were quantified with the aid of a computer program (Olympus Software Analysis, Cell Vision Version, Hamburg, Germany).

All data are presented as arithmetic means [+ or -] standard errors of the means (SEM). One-way-ANOVA followed by Dunnett's post hoc test for multiple comparisons was performed to compare the differences between controls (ovx) and the treatment groups (Prism[TM], Graph Pad, San Diego, USA). P values < 0.05 were considered statistically significant. Correlation statistics was performed with the same program.

Results

Table 1 details the composition of the food, food intake and the thereof calculated intake of the test extracts and the final bodyweights of the animals. Highest bodyweights were present in the ovx animals and significantly lower values were found in the CR BNO 1055 and in the S-fraction treated ovx rats. Fig. 4 shows the size of the paratibial fat depot (PFD) (Fig. 4a) and serum leptin levels (Fig. 4b) which were largest or highest respectively in the ovx animals and significantly smaller/lower in the BNO 1055 and the S-fraction treated ovx rats. The size of the PFD correlated significantly with serum leptin levels (Fig. 4c) The high serum cholesterol values in the ovx rats were also reduced by CR BNO 1055 and the S-fraction (Fig. 5a) and serum cholesterol correlated also significantly with the size of the PFD (Fig. 5b). Fig. 5c details that the high serum glucose levels in the ovx animals were significantly reduced by CR BNO 1055 and the thereof produced S-fraction. The R-fraction had no significant effect on serum glucose.

The size of Hoffa's fat pad is shown in Fig. 6a. Large fat pads in the knee joint were present in ovx animals and they were significantly smaller in the S-fraction treated animals. Fig. 6b details the thickness of the cartilage tissue of the tibial part of the knee joint which was lowest in the ovx and significantly larger in the BNO 1055 and in the S-and the R-fraction treated animals. The size of Hoffa's fat pad correlated inversely with the height of the cartilage tissue (Fig. 6c).

Discussion

It is well accepted that ovx rats develop obesity and that this leads to a condition similar to the Metabolic Syndrome in men (Seidlova-Wuttke et al. 2003; Zoth et al. 2010). It is also known that adipocytes of the visceral fat depots secrete pro-inflammatory adipokines and cytokines which are the primary factors leading to hypercholesterolemia, arteriosclerosis, heart attacks and finally to the type II diabetes (de Ferranti and Mozaffarian 2008; Rai and Sandell 2011). We showed previously that the PFD as well as abdominal fat depots are large in ovx rats (Seidlova-Wuttke et al. 2003). This is confirmed in the present study in which we also demonstrate that ovx rats have largely increased serum leptin levels, indicating a substantial increase in whole body adipocytes which are the source of leptin. The statistically significant correlation of the size of the PFD with serum leptin indicates that this small fat depot is representative for the whole body fat load. With the present results we confirm also previously published data that CR BNO 1055 prevented ovx induced obesity partially (Seidlova-Wuttke et al. 2003). We now add the information that the active substances belong to the S-fraction. It was surprising to note that the bodyweights of the ovx CR BNO 1055 or S-fraction treated animals changed only marginally. This is most likely due to increased muscle mass in these animals. Correlation analysis with data from all animals indicated that the fat load correlated significantly with serum leptin. Among other cytokines, such as TNF[alpha] and IL 6, the adipokine leptin is involved in generating hyperlipidemia (Espinola-Klein et al. 2011; Othman and Moghadasian 2011; Saggini et al. 2011) explaining the high levels of cholesterol and glucose which, together with adiposity is a typical indicator of a Metabolic Syndrome. The reduction of serum cholesterol and glucose by CR BNO 1055 and the S-fraction but not by the R-fraction makes it likely. A number of biologically active triterpenes and polyphenols were described in many Cimicifuga species, but the concentration of specific triterpenes and polyphenols varied significantly between the different species, particularly between North American and Chinese species (Cicek et al. 2010; Jiang et al. 2006, 2011).

In the present experiments we demonstrated also that ovx rats had high fat load in the knee joints, i.e. Hoffa's fat pads were largest in the ovx animals. This large size of articular cartilage was previously shown to be due to ovx as a treatment of ovx rats with E2 was able to prevent deterioration of joint cartilage tissue (Kapur et al. 2010). It was recently shown that adipocytes of joint fat pads have similar properties as the adipocytes in visceral fat depots because they also secrete pro-inflammatory cytokines which cause destruction of joint cartilage (Gandhi et al. 2011; Hazes and Luime 2011; Rai and Sandell 2011). It was interesting to observe that the S-fraction reduced the size of Hoffa's fat pad and that this reduction of fat tissue in the knee joint was accompanied by a significantly larger thickness of cartilage tissue. Hence, it appears that CR BNO 1055 derived S-fraction has beneficial effects in joints. When calculated over all groups the increase of Hoffa's fat pad in the knee joint following ovx correlated inversely and statistically significantly with the size of the knee joint cartilage tissue, i.e. the larger the articular fat depot the lower articular cartilage tissue. Even though a significant correlation does not prove that the high fat load in the knee joint is the causative factor for the decreased cartilage tissue, it makes such relation likely. This may be an additional reason why obese persons, particularly, those with the android fat distribution, often suffer from osteoarthritis. Hence, it is not only the overweight but also the local production of pro-inflammatory cytokines by joint fat cells that determines the progression of osteoarthritis in the human (Gandhi et al. 2011; Hazes and Luime 2011; Rai and Sandell 2011).

The special extract of Chmicifuga racemosa BNO 1055 was previously shown not to contain estrogenic compounds Carry et al. 2003). Hence, other, non-estrogenic compounds in this extract must be responsible for the observed effects. Therefore, the observation that the saponin containing S-fraction contains the chondroprotective substance(s) whereas the more polar fraction was ineffective was of interest. Further purification of the S-fraction may result in the identification of the chemical nature of the active compound(s) which are likely compounds of the actein type (Einbond et al. 2006). The mechanism of action of CR BNO 1055 remains to be explored. A speculation however, is available. Recently we demonstrated that increased fat tissue in the bone marrow correlated also inversely with the mineral density and microarchitecture of the trabecular apparatus in the metaphysis of the tibia. There is compelling evidence that alipocytes in the bone marrow secrete pro-inflammatory cytokines which inhibit the bone forming osteoblasts. Osteo-, chondro- and myoblasts as well as adipocytes stem all from the same adult mesenchymal stem cells (Chamberlain et al. 2007). The way the stem cells undergo differentiation is determined by switch genes. Activation of the peroxisome proliferator activated receptor gamma (PPAR gamma) causes their differentiation into adipocytes (Kawai et al. 2010; Koppen and Kalkhoven 2010; Takada et al. 2009). Less activation of this receptor resulted in less formation of adipocytes and consequently in less production of harmful cytokines. Therefore, we are currently investigating the possibility that CR BNO 1055 contains PPAR gamma inhibitors, i.e. inhibitors of fat cell formation. There is also some evidence that a triterpene of the actein type in Cimicifuga racemosa inhibits the production of pro-inflammatory cytokines in the bone directly (Qiu et al. 2007). Anti-inflammatory effects of Cimicifuga racemosa have been described (Shimoda et al. 2006; Yang et al. 2009). In one study fucinolic acid, a principle constituent of Cimicifuga racemosa (Jiang et al. 2006, 2011) inhibited TNRx production in a mast cell line (Shimoda et al. 2006). In another study lipopolysaccharide induced TNF[alpha] was potently inhibited by a compound present in Cimicifuga racemosa (Yang et al. 2009) of which the structure was described earlier and identified as cimiciracemate A (Burdette et al. 2002).

In summary, we demonstrated that ovx rats have a high fat load resulting in high serum leptin levels. These parameters correlated well with increased serum cholesterol and insulin. The size of Hoffa's fat pad in the knee joint correlated inversely with the cartilage of knee joints indicating that a high fat load of joint may contribute to the development and progression of osteoarthritis. Many of these ovx induced effects can be prevented by treatment with CR BNO 1055 and its saponins. Hence, Black cohosh extracts may be useful to prevent development of the Metabolic Syndrome and of osteoarthritis.

Conflict of interest

WW is consultant of Bionorica SE. The other authors have no conflict to disclose.

Acknowledgements

This work was funded by the Bayerische Forschungsstiftung AZ-838-08, Germany.

The authors are grateful to graduate engineer Alban Karlseder (Bionorica Research Innsbruck, Austria) for his kind help in the development of the analytical processes.

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Dana Seidlova-Wuttke (a), Nicole Eder (a), Vera Stahnke (a), Markus kammann (c), Gunter Stecher (c), Jutta Haunschild (c), Johannes T. Wessels (b), Wolfgang Wuttke (a), *

(a.) Department of Endocrinology, University Medical Center Gottingen, Germany

(b.) Molecular & Optical Live Cell Imaging, University Medical Center Gottingen. Robert-Koch-Str. 40, D-37075 Gottingen, Germany

(c.) Bionorica SE, Kerschensteiner Str. 11-15, 92381 Neumarkt, Germany

* Corresponding author at: Department of Endocrinology, University Medical Center Gottingen, Robert-Koch-Strasse 40, D-37075 Gottingen, Germany.

Tel.: +49 551 396714: fax: +49 551 396518.

E-mail address: ufkendo@med.uni-goettingen.de (W. Wuttke).

0944-7113/$--see front matter [c] 2012 Elsevier GmbH. All rights reserved.

doi:10.1016/j.phymed.2012.03.001
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Author:Seidlova-Wuttke, Dana; Eder, Nicole; Stahnke, Vera; Kammann, Markus; Stecher, Gunter; Haunschild, Ju
Publication:Phytomedicine: International Journal of Phytotherapy & Phytopharmacology
Article Type:Report
Geographic Code:4EUGE
Date:Jun 15, 2012
Words:5185
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