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Female Reproductive Tract |
a Department of Obstetrics and Gynecology, University of Illinois at Chicago, Chicago, Illinois 60212-7313
b Cell and Molecular Biology, Northwestern University Medical School, Chicago, Illinois 60611
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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human chorionic gonadotropin, signal transduction, uterus
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Chorionic gonadotropin (CG), a glycoprotein hormone, is the major embryonic signal in primates. During implantation and pregnancy, CG is primarily secreted by the syncytiotrophoblast. Our previous in vivo studies have shown that CG, when infused into the baboon's uterine cavity, modulated the receptive endometrium during the implantation window [4]. These effects included a plaque response in the luminal epithelium, an induction of 
-smooth muscle actin (-SMA) in the subepithelial stromal fibroblasts and an increase in glycodelin expression and secretion in the glandular epithelium. In the human, in vivo infusion of CG into the uterine cavity during the luteal phase also regulates the secretion of several cytokines and growth factors into the uterine fluid [5].
The CG/LH receptor (CG R) is a member of the subfamily of glycoprotein hormone receptors within the superfamily of G protein-coupled receptor (GPCR)/seven-transmembrane domain receptors [6]. Extragonadal CG R has been reported in both reproductive and several nonreproductive organs in human [7–10]. The structural and functional properties of these extragonadal CG R, especially in the endometrium, are still controversial [11, 12]. However, these receptors are functional based on the in vivo studies in baboons [4] and human and in vitro studies with cells obtained from the human endometrium [13].
In gonadal tissues, binding of CG to its receptor generates signal transduction through the associated G proteins. The classical responses are an increase in cAMP and consequent activation of protein kinase A (PKA) upon activation of the adenylyl cyclase (AC) pathway and an increase in intracellular calcium through inositol triphosphate (IP3)/phospholipase A2 (PLA2) pathway. The possible activation of protein kinase C (PKC) through diacylglycerol (DAG) has also been suggested [14].
The major cell types of the uterine endometrium of the baboon undergo marked cellular changes in response to CG during the window of uterine receptivity. The luminal epithelial cells undergo endoreplication and form epithelial plaques, while the glandular epithelial cells increase their secretory activity [4]. Therefore, the objective of this study was to explore the signal transduction cascade activated by CG in the epithelial cells that in turn may modulate the mitogenic and secretory responses in the uterine epithelium.
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MATERIALS AND METHODS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Recombinant human chorionic gonadotropin CG was obtained from Dr. A.F. Parlow (National Hormone and Pituitary Program, Harbor-UCLA Medical Center, Torrance, CA). The 125I-labeled CG (4674 Ci/mmol) was purchased from Perkin Elmer Life Sciences (Boston, MA). A phosphotyrosine-RC20 antibody (catalog no. E120H) was from Transduction Laboratories, Inc. (Lexington, KY). Monoclonal phospho-extracellular signal-regulated protein kinases 1 and 2 (ERK 1/2) (Thr202/Tyr204) E10 antibody (catalog no. 9106), polyclonal ERK 1/2 (catalog no. 9102), and polyclonal phospho-cAMP regulatory element-binding protein (CREB) (Ser133, cat no. 9191) antibodies were from Cell Signaling Technology, Inc. (Beverly, MA). Monoclonal -tubulin clone B-5-1-2 (catalog no. T5168) antibody, IBMX (3-isobutyl-1-methylxanthine), and forskolin (7-acetoxy-1, 6ß, 9-trihydroxy-8, 13-epoxy-labd-14-en-11-one) were from Sigma Chemical Company (St. Louis, MO). Horseradish peroxidase-conjugated secondary antibodies were from Bio-Rad Laboratories (Hercules, CA). Enhanced chemiluminescence kit and prostaglandin E2 (PGE2) enzyme immunoassay kit were from Amersham Life Sciences (Arlington Heights, IL). PD 98059 (2'-amino-3'-methoxyflavone), H-89 {N-[2-((p-bromocinnamyl)amino)ethyl'-5-isoquinolinesulfonamide, 2HCl}, and cAMP enzyme immunoassay kit were from Biomol Research Laboratories, Inc. (Plymouth Meeting, PA). TriReagent was from Molecular Research Center (Cincinnati, OH). All cell culture supplies were obtained from Gibco BRL (Gaithersburg, MD). Other reagents of cell culture grade were purchased from Fisher Scientific (Itasca, IL), Sigma, or Boehringer-Mannheim (Indianapolis, IN).
Isolation of Baboon Endometrial Epithelial (BE) Cells
Baboon endometrial (BE) tissue was obtained from adult female baboons (Papio anubis) following ovarian hyperstimulation (n = 2) or during the midluteal phase of the menstrual cycle between Days 9 and 12 postovulation (PO) (n = 4). The endometrial tissues were obtained either by endometrectomy or hysterectomy. All animal studies were approved by the Animal Care Committee at the University of Illinois at Chicago. Epithelial cells were isolated from baboon endometrial tissues as previously described [15], with the following modifications. Briefly, the endometrial tissues were cut into 1–3-mm3 pieces and digested with 0.5% collagenase and 0.02% deoxynuclease in calcium- and magnesium-free Hanks balanced salt solution (HBSS) in a shaking water bath at 37°C for 1 h. After centrifugation (200 x g, 5 min), the pellet was resuspended with 5 ml of HBSS and passed through a 95-micron pore-size nylon mesh. The retentate was redigested with 0.5% collagenase, 0.02% deoxynuclease, 0.1% pronase, and 0.2% hyaluronidase in HBSS in a shaking water bath at 37°C for another 30 min. Following centrifugation at 200 x g for 5 min, the supernatant was collected. The pellet was resuspended with 5 ml of HBSS and passed through a 95-micron pore-size nylon mesh. The retentate from this step was mixed with the collected supernatant and digested in a shaking water bath at 37°C for another 30 min. The filtrate was passed through a 20-micron pore-size nylon mesh twice. At each time, the retentate, which contained enriched glandular epithelial cells, was resuspended in HBSS and collected. Following the last digestion, the mixture was passed through a 95-micron pore-size nylon mesh. The filtrate was passed through a 20-micron pore-size nylon mesh twice. Each time the retentate, containing enriched glandular epithelial cells, was collected and resuspended in HBSS. The final solutions were mixed and centrifuged at 200 x g for 5 min. The cell pellet was resuspended in culture medium, which consisted of Dulbecco Modified Eagle Medium (DMEM) with D-valine, 0.1 mM sodium pyruvate, penicillin-streptomycin; 10 000 units-10 mg/ml (P/S), and 10% heat-inactivated and charcoal-stripped fetal bovine serum (SFBS), and the cells were incubated for 24 h at 37°C in a humidified atmosphere of 5% CO2–95% air. Medium was changed after 24 h and then every other day. BE cells were cultured for 5–7 days prior to the initiation of the experiments. The purity of the attached cells was determined by immunocytochemistry using an antibody against cytokeratin (DAKO, Carpenteria, CA) to confirm the epithelial phenotype and an antibody against vimentin (Zymed, San Francisco, CA) to confirm the contaminating stromal fibroblast phenotype. The purity of the glandular epithelial cell preparation used in these studies was >90%.
Cell Lines
A human endometrial epithelial cell line (HES) was used for comparative studies. These cells were isolated from a proliferative, noncancerous endometrium at hysterectomy and spontaneously immortalized during culture [16]. They have similar immunocharacteristics to primary epithelial cells from the baboon. They also express estrogen and progesterone receptors [17]. For these studies, they were cultured in DMEM, 0.1 mM sodium pyruvate, P/S, and 10% SFBS. Medium was changed every other day. The cells were subcultured every 4–5 days.
CHO-LH cells [18] were used as positive controls. They were cultured in Minimum Essential Medium medium (-MEM), 0.1 mM sodium pyruvate, P/S, geneticin (G418 sulfate, 600 µg/ml), and 10% SFBS. Medium was changed every other day. The cells were subcultured every 4–5 days.
The presence of CG/LH receptors on each of the cell types used in these studies was confirmed by reverse transcriptase and polymerase chain reaction (RT-PCR). The specific primers were designed against sequences in exon 11 that code for the transmembrane domain and between exon 5 and 8 for the extracellular domain. Amplification of the extracellular domain in BE and HES cells required nested PCR of the initially amplified product.
Preparation of Cell Membranes and Ligand Binding
Baboon corpora lutea (CL) were obtained on Day 10 postovulation. CHO-LH and HES cells were grown to confluence in the appropriate media. Membrane preparations were made by homogenizing the CL and scrapped cells using a dounce homogenizer in a buffer containing 50 mM Tris-HCl (pH = 7.4), 0.1 mM PMSF, and 0.25 M sucrose. The homogenates were centrifuged for 80 min at 100 000 x g. For the affinity cross-linking experiments, 125 µg of membrane protein was incubated overnight at 4°C with 1 x 106 cpm 125I-labeled CG. An additional set of membrane preparations was preincubated with 25 nM CG for 30 min before the addition of the radiolabeled CG. The membranes were affinity cross-linked by incubating the samples with 0.1 mM of disuccinimidyl suberate for 30 min at 4°C [19]. Following extensive washing, each sample was resuspended in Laemmli buffer, boiled for 5 min, and then separated on a 10% SDS-PAGE gel. The gel was either dried or blotted onto nitrocellulose membranes and exposed to Kodak Biomax film for 7–21 days.
Preparation of Cells
For all in vitro experiments in this study, the cells were prepared according to the following scheme. Each cell type was cultured in its particular culture medium plus 10% SFBS until the cells were 60%–70% confluent. The medium was then changed to 2% SFBS until the cells were 80%–100% confluent (80%–90% confluent for BE cells). To prevent the confounding effects of SFBS on cell signaling studies, the cells were rinsed twice with serum-free medium and were maintained in this medium for 14 h in 5% CO2:95% air at 37°C. After 14 h, the cells were rinsed twice with serum-free medium and stabilized in this medium for another 4 h prior to the initiation of the experiments. In the experiments with PD 98059, a specific mitogen-activated protein kinase (MEK 1/2) inhibitor [20], the cells were pretreated with this inhibitor for 1 h prior to stimulation with CG. In the experiments with H-89, the PKA inhibitor, the cells were pretreated with this inhibitor for 30 min prior to stimulation with CG. Inhibitors were added at the concentrations indicated in the figure captions. CG was used at a concentration of 10 nM (bioactivity = 1.8 IU/ml; NIH/NHPP) in all experiments. This concentration approximates the measurable levels of CG in the baboon blastocyst culture medium [21].
Measurement of Intracellular cAMP Levels
HES and CHO-LH cells were grown on 12-well tissue culture plates. BE cells were grown on 24-well tissue culture plates. Krebs-Ringer solution was equilibrated in 5% CO2 for 24 h prior to the initiation of the experiments. The cells were washed twice with Krebs-Ringer solution and equilibrated in this solution for 30 min at 37°C. The medium was then aspirated and Krebs-Ringer with 0.5 M IBMX was added for another 15 min. The cells were then treated with CG (10 nM) for 5, 15, 30, and 60 min. In addition, a dose-response effect was also determined by treating the cells with either 10 or 100 nM CG for 15 min. Forskolin (10 M), the adenylyl cyclase (AC) activator, was used as a positive control at the 15-min time point. At the end of the incubation, the cells were lysed with 0.1 M HCl and stored at -20°C. Intracellular cAMP concentrations were determined by using a cAMP enzyme immunoassay kit.
Measurement of Adenylyl Cyclase Activity
Membranes from HES cells were prepared by homogenizing cells in 10 mM Tris-HCl, pH 7.0, 1.0 mM EDTA, and 27% sucrose, with a glass-glass Dounce homogenizer, followed by centrifugation at 1000 x g for 5 min to remove nuclei and cell debris and then at 10 000 x g for 30 min. The final pellet was resuspended in 10 mM Tris HCl and aliquots frozen at -70°C [22]. AC activity in 
30 µg membrane protein was measured in a 10-min reaction at 30°C in the presence of 25 mM 1,3 bis-[tris(hydroxymethyl)-methylamino] propane (pH 7.2), 0.4 mM EDTA, 1 mM EGTA, 0.2 mg/ml creatine phosphokinase, 20 mM phosphocreatine, 5 mM MgCl2, 100 µM GTP, 1 mM ATP, and 1 mM [3H]cAMP (20 000 cpm]), [-32P]ATP (10 µCi, 100–200 cpm/pmol), 10 µg/ml BSA, 10 µg/ml CG, or 100 µM forskolin. The reaction was stopped and [32P]cAMP was purified and quantified [22–24].
Preparation of Cell Lysates and Immunodetection
HES and CHO-LH cells were grown on 100-mm2 tissue culture dishes. BE cells were grown on 60-mm2 tissue culture dishes due to the limited availability of primary cells. Following each of the respective treatments, the cells were rinsed twice with ice-cold PBS, pH 7.4, and lysed on ice with 600 µl of lysis buffer (200 µl for BE cells) as previously described [25]. Protein concentration was determined using the Bradford assay. Cell lysate proteins (15–50 µg) were separated by 8% SDS-PAGE under reducing conditions. The separated proteins were transferred into polyvinylidene difluoride (PVDF) membranes. The immunodetection procedures for each antibody followed the protocols provided by the manufacturers. Immunocomplexes were visualized by enhanced chemiluminescence.
Measurement of PGE2 Levels
HES cells were grown on 12-well tissue culture plates in triplicate and subjected to various treatments. Following each of the respective treatments, the medium was collected and stored at -70°C. The PGE2 concentration in the cell culture medium was determined by using a PGE2 enzyme immunoassay kit from Amersham Life Sciences. The sensitivity of the assay was 2.5 pg/ml of medium.
Statistical Analyses
One-way analysis of variance was used to test the null hypothesis of group differences, followed by a two-tailed Student t-test for pairwise comparisons. Each experiment was repeated three times in triplicate and a P value of <0.05 was considered significant.
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RESULTS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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In the initial study, the presence of the CG/LH receptors in HES and CHO-LH cells were confirmed by ligand affinity cross-linking studies. Baboon corpus luteum (CL) membranes were used as a positive control. In baboon CL and CHO-LH cells, the predominant affinity cross-linked band had an approximate molecular weight of 80 kDa (Fig. 1, arrow, lanes 1 and 2). HES cells also showed a band of similar molecular weight, albeit at a lower intensity (Fig. 1, lane 3). The specificity of the ligand receptor complex was confirmed by competition with unlabeled ligand (Fig. 1, lanes 4–6). Semiquantitative RT-PCR analysis and Western blot analysis of RNA and membrane extracts from CHO-LH and HES cells also confirmed that both mRNA and protein for the LH/CG receptor were in much lower amounts in the HES cells in comparison with CL and CHO-LH cells (data not shown).
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CG Does Not Induce cAMP Production or the Phosphorylation of CREB in Endometrial Epithelial Cells
The classical signal transduction pathway induced by CG is the activation of the AC-cAMP-PKA pathway. We chose to determine if CG could activate this pathway in endometrial epithelial cells. Intracellular cAMP concentrations were measured following CG stimulation for 5, 15, 30, and 60 min (Fig. 2, A–C). Stimulation of BE (Fig. 2A) and HES (Fig. 2B) cells with CG (10 nM) showed no significant increase in cAMP at any of the observed times. Similar responses from BE, HES, and CHO-LH cells were observed when the concentration of CG was increased to 100 nM and treatment time was 15 min (Fig. 3). Only CHO-LH cells (Fig. 2C) showed significant increases in cAMP production in response to CG stimulation at all observed times, with the highest response seen at 5 min. However, the AC enzymes of the three cell types were functional because forskolin (10 M), a direct activator of AC, induced robust increases in cAMP production (Fig. 2, A–C) at 15 min. Consistent with the cellular cAMP data, forskolin but not CG activated AC in a HES cell membrane preparation (Fig. 2D).
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Activation of the AC-cAMP-PKA pathway results in several cellular biological responses. One of these is the phosphorylation of the nuclear transcription factor cAMP regulatory element-binding protein (CREB). As a readout of a typical cAMP response, we therefore determined whether CG stimulated CREB phosphorylation in BE, HES, and CHO-LH cells (Fig. 4). Phosphorylation of CREB was not evident in BE cells. In HES cells, stimulation with CG did not induce an increase in the baseline levels of p-CREB. In contrast, CREB phosphorylation was significantly increased in CHO-LH cells in response to 10 nM CG (Fig. 4). These results further substantiate that CG action in the endometrial epithelial cells does not involve immediate activation of the cAMP/PKA pathway.
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CG Induces Phosphorylation of Proteins in HES Cells
Because classical activation of the AC-cAMP-PKA pathway was not evident following CG stimulation in both BE and HES cells, we chose to determine what other signal transduction pathways were activated by CG. Due to the limited availability of BE cells, we used HES cells as the primary cell model. Western blot analysis of HES cell lysates using a phosphotyrosine antibody revealed phosphorylation of several proteins (approximately 38, 42, 54, 73, 116, 158 kDa) following stimulation with CG (10 nM) for 10 and 20 min (Fig. 5).
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CG Activates PKA-Independent Phosphorylation of ERK 1/2 in Endometrial Epithelial Cells
It is well established that the activation of various GPCRs can lead to the activation of the MAPK pathway and consequent cellular responses. The ability of the CG/LH receptor to signal via the MAPK/ERK pathway was previously reported in a heterologous cell model [26] and in porcine granulosa cells [27]. We therefore sought to determine whether CG also activated the MAPK pathway in HES cells because the major phosphorylated proteins evident in response to CG stimulation had a molecular weight of approximately 42 kDa, which corresponds to the ERK subfamily of MAPK. Using a specific antibody against the phosphorylated forms of ERK1/2, our results demonstrate that ERK 1/2 were rapidly phosphorylated in response to CG stimulation in comparison with controls (Fig. 6A). In HES cells, this response was MEK dependent because incubation with PD 98059 inhibited the phosphorylation of ERK 1/2 in both a time- and dose-response manner (Fig. 6B). In addition, this response was PKA independent because H-89, the PKA inhibitor [28], did not inhibit phosphorylation of ERK 1/2 in HES cells, in contrast with its effects in CHO-LH cells (Fig. 7, A and B).
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CG Induces PGE2 Production in Endometrial Epithelial Cells
The implantation process in several species is similar to an inflammatory response. This response is characterized by prominent endometrial stromal edema due to an increase in vascular permeability. Cyclooxygenase-2 (COX-2) and PGE2 have been shown to be the important mediators of this event [29]. In the baboon, COX-2 is expressed in the glandular and luminal epithelial cells during the luteal phase [30], and its expression is maintained in the epithelial cells following the infusion of CG into the uterine lumen. Because COX-2 is the rate-limiting enzyme in prostaglandin biosynthesis, we measured the PGE2 concentrations in the culture media of the HES cells following CG stimulation. Within 2 h, a significant increase in PGE2 was detectable in response to CG. However, PD 98059 inhibited CG-stimulated PGE2 production (Fig. 8). These results suggest that activation of ERK 1/2 by CG activates a cascade of events that ultimately increases PGE2 synthesis by endometrial epithelial cells.
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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In gonadal tissues, both CG and LH signal via the CG R to stimulate the AC-cAMP-PKA pathway [33]. The presence of this classic pathway was confirmed with our results using CHO-LH cells. Our results, however, indicate that, in epithelial cells of endometrial origin (human and baboon), CG does not activate the AC-cAMP-PKA pathway. Instead, the stimulation with CG leads to the phosphorylation of ERK 1/2. This suggests that CG may activate a different set of GPCR signal transduction pathways in endometrial epithelial cells. The lack of stimulation of the AC-cAMP-PKA pathway in endometrial epithelial cells could be due to the presence of different AC isoforms, an increase in phosphodiesterase activity, deficient receptor coupling to Gs, or competition for overlapping effector sites with other G proteins [34]. However, data in HES cell membranes showing that CG does not promote AC activation suggests that the inability of CG to raise cAMP levels is not attributable to increases in phosphodiesterase activity or inhibition of cAMP production. Identification of these alternate signaling pathways is currently under investigation.
Our results also showed that CG can rapidly induce phosphorylation of ERK 1/2 both in CHO-LH and endometrial epithelial cells. Phosphorylation of ERK 1/2 in CHO-LH cells is PKA dependent, consistent with results in porcine granulosa cells [27] and rat granulosa cell lines [35] treated with LH. Crosstalk between ERK 1/2 and cAMP has also been shown to be present in other cell types [36]. In contrast with CHO-LH cells, phosphorylation of ERK 1/2 in HES cells is PKA independent. This novel result further confirms our data that CG does not activate AC to elevate cAMP and suggests that unique signal transduction pathways are activated by CG in the endometrial epithelial cells. Knowledge regarding the upstream events and the role of ERK 1/2 in CG actions in endometrial epithelial cells is absent. The ERK kinases function as integrators of mitogenic and other signals originating from distinct classes of cell surface receptors, such as receptor tyrosine kinases and GPCRs [37]. Binding of diverse extracellular stimuli to GPCR can activate these kinases via several signal transduction pathways [38]. Phosphorylation of ERK 1/2 regulates processes in the cytoplasm, nucleus, cell membrane, and cytoskeleton. The changes in cytoskeletal proteins are also evident in the baboon uterus at the time of uterine receptivity and implantation and are modulated by CG [4, 39]. In addition, phosphorylated ERK 1/2 are capable of inducing cellular proliferation and differentiation. This in turn may contribute to the formation of epithelial plaques in the luminal epithelium and the increased secretory activity of glandular epithelial cells in response to the in vivo infusion of CG [4].
In HES cells, the ERK 1/2 pathway activated by CG increases PGE2 production possibly through the regulation of COX-2 activity. COX-2 and PGE2 play important roles in several aspects of implantation in primates and other species [29, 40]. In vitro studies also suggest that CG regulates endometrial blood flow by increasing the secretion of the vasoactive PGE2 [13]. In addition, PGE2 released from the epithelial cells may act in an autocrine manner through its cognate receptor and cause the upregulation of COX-2 [41]. A similar pathway where PGE2 could induce the upregulation of COX-2 through a cAMP-dependent pathway has been shown to be present in an endometrial adenocarcinoma cell line, HEC-1B cells [42]. Thus, the increase in PGE2 in epithelial cells in response to CG stimulation may be critical to prepare the endometrium for blastocyst implantation.
Our results, however, differ from two other studies that showed that CG could activate the AC pathway in the endometrial epithelial cells, resulting in the increase of COX-2 expression and PGE2 production [13, 43]. One possibility for this discrepancy is the type of cell line used. Previous studies [43] utilized HEC-1B cells derived from the endometrial adenocarcinoma cells, which may have a greater LH/CG receptor density compared with normal endometrium [44, 45]. In addition, these studies were done in the presence of steroids. Estrogen and progesterone have been shown to induce the AC and its activator, Gs, in the endometrium [46]. Another possibility for this discrepancy is the differences in cAMP measurements both in terms of time and the source of cAMP [13]. The patterns of immediate signal transduction induced by CG in BE and HES cells in the current study are similar to those seen in CHO-LH cells, which demonstrated rapid response both in intracellular cAMP production and phosphorylation of ERK 1/2. Conceivably, over an extended period of time, PGE2 generated in response to CG could increase intracellular cAMP, leading to an increase in COX-2 mRNA via the PKA pathway [36].
In summary, our results show that CG acts directly on primate epithelial endometrial cells in a cAMP- and PKA-independent manner to stimulate ERK 1/2 phosphorylation. This novel signal transduction pathway is functional and leads to an increase in COX-2 mRNA and PGE2 production. We can only speculate that this alternative signal transduction pathway may be mediated by an alternate spliced form of the CG R in a manner similar to that of the FSH receptor [47]. Alternatively and perhaps more likely, this cAMP/PKA-independent pathway may prevent rapid receptor desensitization in the presence of high concentrations of ligand that would be present during implantation and early embryonic development, assuring that the CG is able to modulate the endometrial receptor to develop an appropriately receptive endometrium that is essential for embryo implantation.
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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2 Correspondence: Asgerally T. Fazleabas, The University of Illinois at Chicago, Department of Obstetrics and Gynecology, 820 South Wood Street (M/C 808), Chicago, IL 60612-7313. FAX: 312 996 4238; asgi{at}uic.edu
Received: 27 May 2002.
First decision: 11 June 2002.
Accepted: 22 August 2002.
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REFERENCES |
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