(Hypertension. 2000;35:1129.)
© 2000 American Heart Association, Inc.
Scientific Contributions |
Characterization of Murine Vasopressor and Vasodepressor Prostaglandin E2 Receptors
From the Division of Nephrology (Y.Z., Y.G., A.S., S.B., R.M.B., M.D.B.), the Departments of Molecular Physiology and Biophysics and Veterans Administration Medical Center (M.D.B.), and the Department of Pharmacology (R.M.B.), Vanderbilt University School of Medicine, Nashville, Tenn.
Correspondence to Dr Matthew D. Breyer, Division of Nephrology, S-3223 MCN, Vanderbilt University Medical Center, Nashville, TN 37232. E-mail matthew.breyer{at}mcmail.vanderbilt.edu
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Abstract—Four E-prostanoid (EP) receptors, designated EP1, EP2, EP3, and EP4, mediate the cellular effects of prostaglandin E2 (PGE2). The present studies pharmacologically characterize the vasopressor and vasodepressor EP receptors in wild-type mice (EP2+/+ mice) and mice with targeted disruption of the EP2 receptor (EP2-/- mice). Mean arterial pressure (MAP) was measured via a carotid artery catheter in anesthetized male mice. Intravenous infusion of PGE2 decreased MAP in EP2+/+ mice but increased MAP in EP2-/- mice. Infusion of EP3-selective agonists, including MB28767, SC46275, and sulprostone, increased MAP in both EP2+/+ and EP2-/- mice. Pretreatment with SC46275 desensitized mice to the subsequent pressor effect of sulprostone, but the vasodepressor effect of PGE2 in EP2+/+ mice remained intact. Although PGE2 alone increased MAP in EP2-/- mice, prior desensitization of the pressor effect with SC46275 allowed a residual vasodepressor effect of PGE2 to be seen in the EP2-/- mice. An EP4-selective agonist (prostaglandin E1-OH) functioned also as a vasodepressor in both EP2-/- and EP2+/+ mice. High levels of EP3 receptor mRNA were detected in mouse aortas and rabbit preglomerular arterioles by nuclease protection, with lower expressions of EP1, EP2, and EP4 mRNA. The findings suggest that combined vasodepressor effects of EP2 and EP4 receptors normally dominate, accounting for the depressor effects of PGE2. In contrast, in EP2-/- mice, EP4 receptor activity alone is insufficient to overcome the EP3 vasopressor effect. These findings suggest that a balance between pressor and depressor PGE2 receptors determines its net effect on arterial pressure and that these receptors may be important therapeutic targets.
Key Words: hypertension, sodium-dependent • blood pressure • prostaglandins
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Introduction |
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Prostaglandins are critical regulators of vascular tone and arterial pressure.1 2 3 4 5 Inhibition of endogenous prostaglandin synthesis by NSAIDs may result in systemic hypertension or compromise the control of blood pressure in subjects with preexisting salt-sensitive hypertension.3 5 Prostaglandin E2 (PGE2) is a potent vasodilator in several vascular beds and directly relaxes preconstricted vascular rings.6 Conversely, PGE2 directly constricts smooth muscle in other tissues, including ileum and vas deferens.7 8 These opposing effects of PGE2 are thought to be mediated by distinct G-protein–coupled E-prostanoid (EP) receptors, designated EP1, EP2, EP3, and EP4.7 These receptors may be distinguished by their functional effects and by their affinity for structural analogues of PGE2. At least 2 constrictor EP receptors, designated EP1 and EP3, exist.7 8 9 10 11 The EP1 receptor signals through increased cell calcium and is highly active in vas deferens and ileal smooth muscle.7 8 12 13 The EP3 receptor signals through an inhibitory G protein (Gi) to decrease cAMP and is selectively activated by MB28767 and SC46275.11 14 15 There are also 2 distinct EP receptors that relax smooth muscle, designated EP2 and EP4.16 17 EP2 and EP4 receptors directly dilate vascular smooth muscle rings in vitro.16 17 Both these receptors increase cAMP but may be distinguished by their differential sensitivity to the EP2-selective agonist butaprost and the EP4-selective agonist prostaglandin E1 (PGE1)-OH.15 17
An important role for EP receptors in regulating systemic blood pressure has been suggested by recent studies in mice with targeted disruption of these receptors. Disruption of the EP2 receptor is associated with the development of salt-sensitive hypertension.18 Importantly, these mice also displayed an aberrant effect of PGE2 infusion on MAP, which increased blood pressure in EP2 knockout mice as opposed to the typical decrease in blood pressure observed in control mice.18 This finding suggests the importance of both pressor and depressor EP receptors in regulating systemic blood pressure. Recent studies have determined the affinity of prostaglandin analogues for all the cloned mouse prostanoid receptors, facilitating the interpretation of pharmacological studies examining the role of EP receptors in mice.15 The present studies were undertaken to pharmacologically characterize the pressor and depressor EP receptors mediating the hemodynamic effects of PGE2 infusion in the mouse.
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Methods |
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Chemical Reagents
PGE2 and PGE1-OH were purchased from Biomol. Sulprostone was provided by Berlex Laboratories (Cedar Knolls, NJ). MB28767, which was generously provided by Michael Caton (Rhone-Poulanc Rorer, Dagenham, England), and SC46275, which was provided by Drs Richard Marks and Edward Drower (Searle R&D, Skokie, Ill), were dissolved in ethanol.
Animal Preparation
C57BL/6 mice were purchased from Harlan (Indianapolis, Ind).
EP2-deficient mice were developed as previously
described.18 F2 wild-type
(EP2+/+) and
EP2-null
(EP2-/-) mice were littermates
produced from intercrossing F1 heterozygous
(EP2+/-) mice. Experiments were
conducted in male mice age 8 to 12 weeks. All mice were weaned at 3
weeks of age and fed a standard chow diet. Mice were housed under
controlled conditions (temperature 21±1°C, humidity 60±10%,
lighting for 8 to 20 hours). Genotypes of mice were routinely
determined by Southern analysis of genomic tail DNA. The
wild-type (4.3-kb) and recombinant (7.5-kb) XbaI fragments
were identified by using a 3' XbaI/SacI fragment
as a probe.
Blood Pressure Measurement
Male F2
EP2+/+ and
EP2-/- mice and C57BL/6 mice,
age 12 to 16 weeks and 20 to 25 g in body weight, were
anesthetized with 80 mg/kg ketamine (Fort Dodge
Laboratories) and 8 mg/kg inactin (BYK) by
intraperitoneal administration. Mice were placed on
a temperature-controlled pad. After tracheostomy, PE-10 tubing was
inserted into the right carotid artery, a jugular vein catheter was
placed for infusion, and a urinary bladder catheter was inserted for
urine collection. Blood pressure was measured with a Cobe CDX II
transducer connected to a blood pressure analyzer (BPA 400,
Micromed). The readings of blood pressure and heart rate were
equilibrated for 30 to 60 minutes until stable values were obtained.
The test agents (PGE2, sulprostone, MB28767,
SC46275, and PGE1-OH) were mixed with 25 µL of
saline and injected as a bolus via the jugular vein over 
20 seconds.
Blood pressures, including systolic, diastolic, and
mean arterial pressure (MAP), and heart rates were
recorded continuously on a thermal printer or computerized data
record.
For measurement of blood pressure in conscious mice, we followed the technique of Mattson.19 Animals were preanesthetized with methoxyflurane and sodium pentobarbital (50 mg/kg IP). With use of an aseptic technique, femoral artery catheters were placed for MAP measurement, and femoral venous catheters were placed for infusion. Three days after surgery, PGE2 (200 µg/kg) or SC46275 (20 µg/kg) was administered as a 100 µL bolus, and blood pressure was recorded by use of a Cobe CDX II transducer (described above).
Preparation of cDNA Probes
Mouse EP1 (649-bp),
EP2 (420-bp), EP3 (438-bp),
and EP4 (350-bp) cDNA fragments were generated by
reverse transcription–polymerase chain reaction from mouse kidney and
ileum total RNA and were cloned into pCR-TOPO vector (Invitrogen).
Rabbit EP1 (223-bp), EP2
(345-bp), EP3 (466-bp), and
EP4 (368-bp) cDNA fragments were also generated
by reverse transcription–polymerase chain reaction from rabbit kidney
and uterus and were also cloned into pCR-TOPO vector (Invitrogen).
Mouse ß-actin cDNA was obtained from Ambion Inc. Antisense and sense
riboprobes were synthesized in vitro with the use of an appropriate RNA
polymerase (Maxiscript, Ambion) and [32P]UTP
for RNase protection assays.
Solution Hybridization/RNase Protection Assay
RNase protection assays were performed as described
previously.20 Briefly, plasmids containing rabbit or mouse
EP1, EP2,
EP3, and EP4 and rabbit
GAPDH or mouse ß-actin inserts, described above, were linearized with
appropriate restriction enzymes. Radioactive riboprobes were
synthesized from 1 µg of linearized plasmid in vitro by use of a
Maxiscript kit (Ambion) for 1 hour at 37°C in a total volume of 20
µL. The reaction buffer contained 10 mmol/L dithiothreitol,
0.5 mmol/L ATP, CTP, and GTP, 2.5 mmol/L UTP, and 5 µL of
800 Ci/mmol [
-32P]UTP at 10 mCi/mL (Dupont
NEN). Hybridization buffer included 80% deionized formamide, 100
mmol/L sodium citrate, pH 6.4, and 1 mmol/L EDTA (RPA II, Ambion).
Total RNA (20µg), isolated by Trizol-Reagent (GIBCO-BRL), was
incubated at 45°C for 12 hours in hybridization buffer with
5x104 cpm labeled riboprobes. After
hybridization, ribonuclease digestion was carried out at 37°C for 30
minutes, and precipitated protected fragments were separated on 4%
polyacrylamide gel at 200 V for 3 hours. The gel was exposed to
Kodak XAR-5 film overnight at -80°C with intensifying screens.
Isolation of Renal Microvessels
Renal preglomerular microvessels were isolated by
following the method of Chaudhari and Kirschenbaum.21 The
renal artery of anesthetized New Zealand White rabbits was
cannulated, and kidneys were perfused with 10 mL of ice-cold normal
saline, followed by 10 mL of a 1% suspension of magnetized iron oxide
(Fe3O4, Aldrich) in
normal saline. The cortex of the kidneys was minced with a tissue press
and homogenized with a Polytron homogenizer
(Brinkmann) at moderate speed for 15 seconds twice. Microvessels were
separated from nonvascular tissue in several washing steps (in 1x PBS)
with the help of a strong magnet held to the outside of the tube.
Washing and separation were repeated after passing the
homogenate through 20-, 21-, and 23-gauge needles,
respectively, until the suspension was mostly free of glomeruli and
other nonvascular tissue. This technique provided a large quantity of
relatively pure preglomerular microvessels, with 10% to
15% of the suspension consisting of attached glomeruli and small
fragments of early proximal tubules.
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Results |
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Different Effects of PGE2 on Blood Pressure in Mice
The dose-dependent effect of PGE2 on MAP pressure was determined in male mice (Table). Baseline MAPs were not significantly different in anesthetized EP2+/+ and EP2-/- mice (108.5±5.2 [n=4] versus 104±19.2 [n=5], respectively). Sixty seconds after PGE2 infusion, MAP was significantly decreased by 10.3±3.2 mm Hg in EP2+/+ mice (Figure 1), whereas MAP was increased by 22.3±7.2 mm Hg in EP2-/- mice. These effects are qualitatively similar to those previously observed in female mice22 and demonstrate the existence of both pressor and depressor EP receptors in mice.
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) and
EP2-/- (
) mice. PGE2 (100
µg/kg) was infused intravenously at time=0 seconds as
described in Methods. *P<0.05 vs baseline MAP (paired
t test). MAP did not change in mice receiving vehicle
alone (not shown).
EP3 Agonists Are Potent Vasopressors
The dose-dependent effects of intravenous infusion of
3 EP3 receptor agonists, sulprostone
(EP3>EP1), MB28767
(EP3), and SC46275 (EP3) on
MAP were examined. As shown in the Table, all 3
EP3 agonists significantly increased MAP. Both
MB28767 and SC46275 infusion (1 to 10 µg/kg) resulted in a prompt and
marked increase in MAP with a progressive return to baseline over 15
minutes (Figure 2). Similarly,
sulprostone, a pressor agonist that acts at the
EP1 and EP3 receptors,
increased MAP in wild-type and
EP2-/- mice, as previously
reported.18 Likewise the pressor effects of 2
EP3 agonists, MB28767 and SC46275, seen in
EP2+/+ mice were identical in
EP2-/- mice (Table).
These pressor effects are not specific for anesthetized mice
because SC46275 (20 µg/kg) also increased MAP in conscious
chronically catheterized mice, from 121.7±8.6 to 132.3±9.2
mm Hg (
MAP 10.7±1.2 mm Hg, n=6, P<0.0003),
whereas PGE2 infusion (200 µg/kg) decreased MAP
from 128.8±8.3 to 106.6±6.4 mm Hg (MAP -22.2±6.2, n=5,
P<0.02) in conscious mice.
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Desensitization of Pressor Effects With Use of
EP3-Specific Agonist SC46275
Experiments were designed to determine whether prior exposure to a
pressor dose of an EP3-selective agonist
desensitized mice to the subsequent effects of a second pressor agonist
(Figure 3A). Pretreatment of mice with 10
µg/kg SC46275 transiently increased MAP as described above and
completely prevented the subsequent pressor effect of sulprostone (20
µg/kg) on MAP. As also described above,
EP2-/- mice characteristically
show a pressor response to infusion of 100 µg/kg
PGE2 (Figure 1); in contrast, wild-type
animals react with a decrease in blood pressure. Prior desensitization
with SC46275 (10 µg/kg) in
EP2-/- mice changed the effect
of PGE2 from a pressor to a depressor response
(Figure 3B), suggesting the existence of a second depressor EP
receptor, distinct from the EP2 receptor in mouse
vasculature. Interestingly, the depressor response observed after
desensitization was significantly greater in
EP2+/+ mice than in
EP2-/- mice (MAP
-35.6±1.7 mm Hg
[EP2+/+, n=4] versus
-18.3±3.7 mm Hg
[EP2-/-, n=4],
P<0.01 by ANOVA).
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EP4 Receptor Agonist PGE1-OH Is
Vasodepressor
To pharmacologically characterize and determine whether this
depressor receptor could be activated in mice without prior
desensitization, the effect of an EP4-selective
agonist, PGE1-OH, was examined. In contrast to
the pressor effects of native PGE2 in
EP2-/- mice,
intravenous administration of
PGE1-OH, decreased MAP in both wild-type and
EP2-/- mice to a similar
extent (Table and Figure 4). At a
dose of 100 µg/kg PGE1-OH, infusion resulted in
a prompt fall in MAP, which was maximal within 1 minute and then
gradually returned to baseline. The maximal decrease in MAP was not
significantly different in wild-type mice and
EP2-/- mice.
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Expression of EP Receptor mRNA in Blood Vessels
RNase protection assays were performed to determine the relative
expression of mRNA for the 4 EP receptors in mouse aorta and rabbit
preglomerular renal vessels. Expression of the
EP3 receptor mRNA predominated in both vessels,
exhibiting a much stronger signal than the other potential constrictor
receptor, the EP1 receptor (Figure 5). Nuclease protections of mRNA from
rabbit preglomerular vessels were repeated on 3 separate
preparations. Densitometry normalized to GAPDH demonstrates that rabbit
EP3 receptor mRNA is 7.7±0.7-fold more abundant
than rabbit EP4 receptor mRNA and 47.8±3.8-fold
more abundant than EP2 receptor mRNA (both
P<0.005 by ANOVA). A similar pattern of expression was
observed in mouse aortas.
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Discussion |
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Accumulating evidence supports an important role for vasodilator prostanoids in preventing hypertension in humans.3 23 Control of blood pressure in patients with essential hypertension is particularly dependent on endogenous vasodilator prostaglandins.22 In mice with targeted disruption of the angiotensin type 2 receptor, increased synthesis of dilator prostaglandins, including PGE2, helps maintain normotension, and these mice develop hypertension when treated with an NSAID.24 The prostanoid receptors maintaining normotension and mediating these dilator responses have been only partially characterized. Targeted disruption of the EP2 receptor is associated with the development of salt-sensitive hypertension in EP2-/- but not wild-type mice.18 Those studies also found that the normal vasodepressor effect of the EP2-selective agonist butaprost was absent in EP2-/- mice. Furthermore, when PGE2, an endogenous ligand, was infused in EP2-/- mice, it increased arterial pressure rather than producing the typical vasodepressor effect observed in EP2+/+ mice. These findings point to the existence of the regulation of blood pressure by multiple EP receptors. The present studies were designed to further characterize the prostaglandin E receptor subtypes regulating arterial pressure in the mouse.
Initial studies confirmed that PGE2 infusion
increased mean arterial pressure in male
EP2-/- mice in a manner
similar to that previously reported for female
EP2-/- mice.18
Conversely, PGE2 functioned as a vasodepressor in
male EP2+/+ mice. Thus,
disruption of the EP2-/-
receptor converts the dominant effect of PGE2
from a vasodepressor to a vasopressor. Some studies have suggested that
the female circulation exhibits greater sensitivity to the
hemodynamic effects of prostaglandins than
does the male circulation.25 The present findings
suggest that this possibility holds true for the effect of
PGE2 on MAP, because there was a tendency for the
depressor effect of PGE2 in male
EP2+/+ mice to be less than in
female EP2+/+ mice (MAP after
PGE2 was -10.3±3.2 mm Hg in males versus
-19.2±5.2 mm Hg in females). However, this trend did not
achieve statistical significance. Further studies are required to
determine whether gender influences the extent of these changes.
Regardless of these considerations, the qualitative effect of
PGE2 on MAP appears similar in female and male
EP2+/+ mice, in which it acts as
a vasodepressor, compared with
EP2-/- mice, in which it acts
as a vasopressor.
The present studies found a potent pressor effect of 2 highly
selective EP3 agonists, MB28767 and SC46275.
SC46275 is 106-fold more potent at
EP3 receptors than at EP1
receptors,11 activating EP1
receptors in ileal smooth muscle only at concentrations 
30
µmol/L, whereas sulprostone comparably activates
EP1 receptors at 20 nmol/L.11 The
potent vasopressor effect of SC46275 suggests an
EP3- rather than an
EP1-mediated effect. Similar findings with
MB28767 support this conclusion. Molecular characterization of all the
cloned murine prostanoid receptors show that MB28767 binds the
EP3 receptor 200-fold more avidly than the
EP1 receptor or any other prostanoid
receptor.15 These findings confirm and extend previous
studies with the EP1/3-selective agonist,
sulprostone,18 and point to a specific role for the
EP3 receptor in regulating vascular tone.
The 3 EP3 agonists used also appear to act via a common mechanism, because pretreatment with an EP3-selective agonist prevented the pressor response to a second EP3 agonist (Figure 3A). The precise mechanism of desensitization remains uncertain but could be consistent with studies showing agonist-induced desensitization and internalization of the cloned mouse EP3 receptor expressed in COS cells.26 Alternatively, the persistence of the EP3 agonist (SC46275) in the circulation because of poor metabolic clearance could lead to ongoing receptor activation.27
Regardless of the desensitization mechanism, pretreatment with EP3-selective analogues did not block the subsequent vasodepressor effect of PGE2, supporting a distinct mechanism for this effect (Figure 3B). It is of note that after SC46275 "desensitization" of the vasopressor E-prostanoid response, a remaining vasodepressor effect of PGE2 in EP2-/- mice was revealed. This supports the persistence of a separate vasodepressor EP receptor in EP2-/- mice, possibly the EP4 receptor. This conclusion is further supported by the observation that even without prior desensitization, PGE1-OH, an EP4-selective agonist, was a depressor in EP2-/- mice. Interestingly, after pretreatment with SC46275, the vasodepressor effect of PGE2 is significantly greater in EP2+/+ mice than in EP2-/- mice, consistent with the possibility that PGE2 activates both EP2 and EP4 depressor receptors in EP2+/+ mice but only the EP4 receptor in EP2-/- mice.
Multiple mechanisms undoubtedly contribute to the effects of PGE2 on blood pressure in the intact animal, including effects on sympathetic nervous activity and renin release and direct effects on vascular tone.6 28 29 30 The present studies used nuclease protection to demonstrate that EP receptor mRNA is expressed in mouse and rabbit vasculature. These studies demonstrate that EP3 receptor mRNA was expressed at significantly higher levels than the EP1, EP2, and EP4 receptor mRNAs. Although it is uncertain whether this EP receptor mRNA expression pattern parallels receptor density, these findings support the results of functional studies suggesting roles for the EP2, EP4, and EP3 receptors in modulating blood pressure. Furthermore, the presence of EP receptor mRNAs in the vasculature suggests that direct effects on vascular tone may contribute to the observed effects of PGE2 infusion on MAP. They additionally support a specific role for the EP3 receptor as a vasopressor receptor in rabbit renal resistance arterioles.
In summary, the present studies provide evidence that the net effect of PGE2 infusion on blood pressure results from a balance between the functional activity of at least 3 distinct EP receptors. Data using an EP4-selective analogue and EP2-/- mice support independent roles for EP2 and EP4 receptors as vasodepressors in the mouse circulation. These findings also suggest a critical role the EP3 receptor as an important vasopressor receptor. No functional evidence supports an independent role for the EP1 receptor as a vasopressor. Given the importance of prostaglandin E receptors in the regulation of blood pressure,18 24 selective agonists and antagonists of vasoactive EP receptors may provide important new therapeutic targets for the treatment of hypertension.
Note Added in Proof
After this manuscript was submitted, another study documenting the
role of EP receptors as vasopressors and vasodepressors in knockout
mice was published by Audoly et al (Am J Physiol.
1999;277:H924–H930).
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Acknowledgments |
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This study was supported by National Institutes of Health (NIH) grant DK-37097 (to M.D.B.) and a Veterans Administration Merit Award (to M.D.B.). Support was also provided by NIH grants DK-46205, and GM-15431 (to R.M.B.). M.D.B. is the recipient of a VA Clinical Investigator Career Development Award.
Received September 13, 1999; first decision October 12, 1999; accepted December 28, 1999.
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  M. Testa, B. Rocca, L. Spath, F. O. Ranelletti, G. Petrucci, G. Ciabattoni, F. Naro, S. Schiaffino, M. Volpe, and C. Reggiani Expression and activity of cyclooxygenase isoforms in skeletal muscles and myocardium of humans and rodents J Appl Physiol, October 1, 2007; 103(4): 1412 - 1418. [Abstract] [Full Text] [PDF]
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 A.-M. Hristovska, L. E. Rasmussen, P. B.L. Hansen, S. S. Nielsen, R. M. Nusing, S. Narumiya, P. Vanhoutte, O. Skott, and B. L. Jensen Prostaglandin E2 Induces Vascular Relaxation by E-Prostanoid 4 Receptor-Mediated Activation of Endothelial Nitric Oxide Synthase Hypertension, September 1, 2007; 50(3): 525 - 530. [Abstract] [Full Text] [PDF]
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 H. Wahn, J. Wolf, F. Kram, S. Frantz, and J. A. Wagner The endocannabinoid arachidonyl ethanolamide (anandamide) increases pulmonary arterial pressure via cyclooxygenase-2 products in isolated rabbit lungs Am J Physiol Heart Circ Physiol, December 1, 2005; 289(6): H2491 - H2496. [Abstract] [Full Text] [PDF]
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 U. G. Friis, J. Stubbe, T. R. Uhrenholt, P. Svenningsen, R. M. Nusing, O. Skott, and B. L. Jensen Prostaglandin E2 EP2 and EP4 receptor activation mediates cAMP-dependent hyperpolarization and exocytosis of renin in juxtaglomerular cells Am J Physiol Renal Physiol, November 1, 2005; 289(5): F989 - F997. [Abstract] [Full Text] [PDF]
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J. D. Imig, M. D. Breyer, and R. M. Breyer Contribution of prostaglandin EP2 receptors to renal microvascular reactivity in mice Am J Physiol Renal Physiol, September 1, 2002; 283(3): F415 - F422. [Abstract] [Full Text] [PDF]
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 T. Grosser, S. Yusuff, E. Cheskis, M. A. Pack, and G. A. FitzGerald Developmental expression of functional cyclooxygenases in zebrafish PNAS, June 11, 2002; 99(12): 8418 - 8423. [Abstract] [Full Text] [PDF]
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 C. N. Fortner, R. M. Breyer, and R. J. Paul EP2 receptors mediate airway relaxation to substance P, ATP, and PGE2 Am J Physiol Lung Cell Mol Physiol, August 1, 2001; 281(2): L469 - L474. [Abstract] [Full Text] [PDF]
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B. L. Jensen, J. Stubbe, P. B. Hansen, D. Andreasen, and O. Skott Localization of prostaglandin E2 EP2 and EP4 receptors in the rat kidney Am J Physiol Renal Physiol, June 1, 2001; 280(6): F1001 - F1009. [Abstract] [Full Text] [PDF]
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