9128A Drug Discovery and Design A – June 2009 Page 1 of 32 pages CONFIDENTIAL
1-62 60 63 3 64 3 65 9 66 4 67 2 68 6 69 3 70 3 71 9 72 8 Total SEAT NUMBER: ..........................................................................
SURNAME: .........................…....................................................
(Block letters) OTHER NAMES: ..........................................................................
(Block Letters) SID: ....................................................…………………………............ FACULTY OF PHARMACY 110 BACHELOR OF PHARMACY DEGREE
Second Year
DRUG DISCOVERY AND DESIGN A (PHAR 2811) June 2009 Time Allowed: 2.5 Hours ANSWER ALL QUESTIONS
•
• Questions 1 - 62 must be answered on the computer sheet provided.
Use a soft pencil to mark the box corresponding to the most correct answer. Mark alphanumeric characters
corresponding to your name and SID, and also write them on the computer sheet.
Marks will NOT be deducted for incorrect answers in the multiple-choice questions. •
• Questions 63 to 72 are to be answered in the spaces provided on pages 23 – 31 of this examination paper.
Non-programmable calculators may be used. •
• All copies of this examination paper are to be returned to the examiner with all pages intact.
None of the examination paper may be removed from the examination room by candidates or supervisors,
nor may any portion be copied. • This examination paper consists of 32 pages, numbered 1-32 inclusive. There are 72 questions, numbered 1- 72
inclusive. Students are asked to check that their booklet is complete, and to indicate that they have done so by
signing below.
I have checked this booklet and affirm that it is complete. SIGNATURE: ___________________________________________
Students finding an incomplete booklet should obtain a replacement from the examination supervisor
immediately. 9128A 1. 2. 3. 4. Drug Discovery and Design A – June 2009 Page 2 of 32 pages The following amino acid side chains are aromatic:
A. Phenylalanine (Phe) and Tyrosine (Tyr). B. Phenylalanine (Phe), Tryptophan (Trp) and Glycine (Gly). C. Tryptophan (Trp), Valine (Val). D. Aspartic Acid (Asp), Glutamic Acid (Glu). E. Glycine (Gly), Valine (Val) and Isoleucine (Ile). L-alanine and D-alanine
A. are present in virtually all proteins. B. are superimposable isomers of each other. C. are enantiomers. D. lack an R group. E. are aromatic. The zwitter ion terminology refers to the amino acid property of
A. hydrophobicity. B. two charges at the one time. C. ionisation of a sidechain. D. chirality for all except glycine and proline. E. containing two sidechains. A protein retained on an affinity chromatography column is usually eluted off the column by A. gradually increasing the salt concentration of the elution buffer. B. adding the protein's free ligand. C. changing the pH of the elution buffer. D. allowing the retained protein to naturally come off the column after the nonspecifically bound proteins have first passed through the resin. E. achieving good quality packing of the matrix material (stationary phase). 9128A 5. 6. 7. 8. Drug Discovery and Design A – June 2009 Page 3 of 32 pages Which of the following experimental techniques is useful for determining high-resolution
3D-protein structures?
A. Circular Dichroism (CD) Spectroscopy. B. Nuclear Magnetic Resonance (NMR) Spectroscopy. C. Powder X-ray crystallography. D. Single crystal X-ray crystallography. E. Amino Acid Sequence analysis. To determine the primary amino-acid sequence in a protein, a useful technique is:
A. Mass Spectrometry. B. Edman degradation. C. Molecular Modelling. D. Nuclear Magnetic Resonance (NMR) Spectroscopy. E. Circular Dichroism (CD) Spectroscopy. An example of a Type 1 receptor is:
A. Adrenoreceptor. B. GABAa Receptor. C. Insulin Receptor. D. Steroid Receptor. E. Nuclear Receptor. When a drug binds tightly to a target, which of the following is INCORRECT?
A. There is a high degree of structural complimentarity between drug and target. B. It is entropically unfavourable for the drug to bind, due to liberation of water
molecules from the active site. C. The electrostatics of drug and target should be mirror images to increase
charge-charge interactions. D. The drug isomeric form is important for steric interaction reasons. E. The protein must remain flexible to allow the drug access to the active site. 9128A 9. Drug Discovery and Design A – June 2009 Page 4 of 32 pages A Ramachandran Plot is calculated for a protein in which the only secondary structure
represented is α-helices. The Plot can be used to:
A. indicate sidechain conformations. B. determine the backbone conformation of β-strands. C. find the range of phi and psi angles for the α-helices. D. predict the protein’s behaviour in ion exchange chromatography. E. determine the prevalence of cis and trans peptide conformations in the protein. 10. As a check on the scanning procedure record an answer of A to question 10. 11. Which of the following is NOT one of the different interactions involved in substrate
binding to an enzyme?
A. Enzymes chiefly bind substrates by noncovalent interactions. B. Enzymes use ionic and hydrogen bonds to bind ligands specifically. C. All amino acids in an active site are involved in the chemical reaction that is
catalysed. D. Enzyme active sites ensure that substrates come together in the correct
orientation for chemical reaction to occur. E. Changes in the active site may change the type of substrate that is bound but not
the chemistry that is catalysed. 12. Which statement about enzyme catalysed reactions is NOT true?
A. Enzymes form complexes with their substrates. B. Enzymes lower the activation energy for chemical reactions. C. Enzymes change the Ks for chemical reactions. D. Many enzymes change shapes slightly when substrate binds. E. Reactions occur at the "active site" of enzymes, where a precise 3D orientation
of amino acids is an important feature of catalysis. 9128A 13. Drug Discovery and Design A – June 2009 Page 5 of 32 pages In describing the reaction rate for a chemical reaction, which of the following statements
about reaction rate is NOT true?
A. Reaction rate is the speed at which the reaction proceeds toward equilibrium. B. Reaction rate is governed by the energy barrier between reactions and products. C. Enzymes can accelerate the rate of a reaction. D. Reaction rates are not sensitive to pH. E. None of these. The following questions refer to the graph below:
160 v (uM/min) 120
80
40
0
0 2 4 6 -40
-80
[S] (mM) 14. 15. Vmax estimated from the graph above is:
A. 60 uM/min. B. 75 uM/min. C. 80 uM/min. D. 120 uM/min. E. 150 uM/min. Km estimated from the graph above is:
A. 1 mM. B. 2 mM. C. 4 mM. D. 5 mM. E. 10 mM. 8 10 12 9128A 16. Drug Discovery and Design A – June 2009 Page 6 of 32 pages Which statement is most CORRECT?
A. 1 kg of human tissue contains about 1 g ATP. B. In a healthy cell, the [ATP] is always much less than the [ADP]. C. The total adenine nucleotide pool ([ATP] + [ADP] + [AMP]) in cells is about
50 mM. D. ATP can be produced in the mitochondria of liver cells and transported in the
blood for use by the muscle. E. At room temperature, a 5 mM solution of ATP will completely hydrolyse into
ADP and phosphate within 1 minute. 17. Which statement about fatty acid oxidation is CORRECT? A. Carnitine is a protein embedded in the cell membrane that allows fatty acids to
enter from the bloodstream. B. Fatty acids are covalently attached to Coenzyme A during the FAD/NAD
catalysed oxidation reactions. C. The oxidation reactions involving FAD/NAD occur only in the cytoplasm. D. Fatty acids attached to Coenzyme A can move freely across the inner
mitochondrial membrane. E. 18. Carnitine is consumed (two carbons at a time) during fatty acid oxidation. Which description of the operation of the Krebs Cycle is MOST CORRECT? A. The cycle goes faster when the electron transport chain is going slowly. B. The pathway is located in both the cytoplasm and the mitochondria. C. The cycle reacts fuel molecules with oxygen to produce carbon dioxide. D. The cycle generates CoA and NADH. E. Most of the ATP in the cell is made directly by enzymes of the Krebs Cycle by
substrate level phosphorylation. 9128A 19. Drug Discovery and Design A – June 2009 Page 7 of 32 pages Which of the following statements is INCORRECT?
A. Electrons can move down the electron transport chain even if proton pumping
from the matrix can not occur. B. Protons are only pumped from the matrix if electrons are passed down the
electron transport chain. C. ATP synthesis at the F1ATPase requires both ADP and phosphate. D. Protons will only come in through the F0F1ATPase if ATP is simultaneously
being made from ADP. E. 20. Protons can pass freely across the outer mitochondrial membrane. Which statement is CORRECT?
A. Two days of continual exposure to a blood glucose concentration of 10 mM
will cause a coma. B. The reaction between proteins and glucose is not an enzyme catalysed process. C. Glycosylation does not affect the function of proteins. D. When blood glucose concentration is 5 mM, the rate of glycosylation is
negligible. E. When blood glucose concentration falls below 4 mM insulin is secreted by the
beta-cells of the pancreas to compensate. 21. Which statement is INCORRECT?
A. It is not practical to measure the glycemic index of meat. B. The reference food used in glycemic index determinations is normally glucose. C. The glycemic index is a relative measure of the post-prandial glucose response
caused by a particular food. D. Amylose containing foods have a lower glycemic index than foods which
mainly contain amylopectin. E. Sucrose has a lower glycemic index than amylopectin starch. 9128A 22. 23. Drug Discovery and Design A – June 2009 Page 8 of 32 pages In white adipose tissue, which process is NOT stimulated by insulin?
A. The rate of glucose uptake. B. Pyruvate dehydrogenase activity. C. Acetyl-CoA carboxylase activity. D. Expression of fatty acyl synthase. E. Lipolysis. Which statement best describes the relationship between the pentose phosphate pathway
(PPP) and lipogenesis?
A. The PPP produces the glycerol needed for esterification of newly formed fatty
acids. B. Lipogenesis provides glycerol 3-phosphate for the PPP. C. Lipogenesis uses NADPH produced by the PPP. D. The PPP provides ATP to fuel lipogenesis. E. The PPP is necessary to provide the carbon dioxide needed to produce malonylCoA. 24. Which statement BEST DESCRIBES chylomicrons?
A. Lipoproteins that carry dietary fat to the peripheral tissues. B. Discs of phospholipids that mop up loose cholesterol in the blood stream. C. Milky droplets formed from the churning of a lipid/salt mixture in the small
intestine. 25. D. Microscopic droplets excreted by tissues that have too much cholesterol. E. An emulsion of fat and protein in the stomach. Which statement regarding the disposal of dietary fat is CORRECT?
A. High Density Lipoprotein (HDL) is formed by the removal of fat from LDL. B. Very Low Density Lipoproteins (VLDL) transport dietary fat from the intestine
to the liver. C. Unsaturated fat goes to the liver, but saturated fat goes to the peripheral tissues. D. A high HDL:LDL ratio is positively correlated with heart disease. E. Peripheral tissues encounter dietary fat before the liver. 9128A 26. 27. 28. 29. Drug Discovery and Design A – June 2009 Page 9 of 32 pages What would be the consequences of inhibition of lipolysis during the first few days of
starvation?
A. Blood ketone body concentration would rise. B. Blood glucose concentration would rise. C. Blood fatty acid concentration would rise. D. There would be fewer substrates for gluconeogenesis in the liver. E. Fatty acid oxidation in the muscles would increase. Which statement about ketone bodies is INCORRECT?
A. Ketone bodies circulate in the blood stream bound to special carrier proteins. B. Ketone bodies can be used the peripheral tissues as well as the brain. C. Ketone bodies can spontaneously decarboxylate to give acetone. D. Ketone bodies are only formed in the liver. E. Ketone body oxidation inhibits glucose oxidation. Which of the following hormones/neurotransmitters does NOT involve the decarboxylation
of a naturally occurring amino acid in its synthesis?
A. Histamine B. Serotonin C. GABA D. Adrenalin E. Thyroxin Considering the thymidylate synthase reaction, which of the following statements is
INCORRECT? The reaction…
A. only occurs in preparation for DNA synthesis B. is part of the de novo purine synthesis pathway C. is indirectly inhibited by methotrexate D. requires folate to supply a methyl group E. cannot be completed if a F atom replaces the H on C5 of the uracil base 9128A 30. 31. 32. Drug Discovery and Design A – June 2009 Page 10 of 32 pages Which of the following statements is INCORRECT?
A. Introns make up ~90% of most genes B. Pseudogenes are thought to result from the action of reverse transcriptases C. Over 90% of the human genome is highly repetitive DNA D. PolyU-polyA is the fastest sequence to reanneal E. Repetitive DNA is often found at the centromeres and the teleomers When performing Cot plot analysis, if a sequence of DNA has a complexity of 100 this
means:
A. The 2 DNA strands are 100 bp long B. The DNA has a unique sequence of 100 bp C. The 2 complementary strands of the DNA take 100 sec to reanneal D. The DNA single strand has a C0t of 100 E. There are 100 copies of a trinucleotide repeating sequence in the DNA Which of the following statements about trinucleotide repeats (TNRs) is CORRECT? A. TNRs do not have to be transcribed to affect an individual. B. TNRs producing polyglutamine tracts significantly change the pI of the affected
protein. C. The common CNG sequence destabilises intrastrand loop formation. D. The TNR tract must be translated above a threshold level to affect an
individual. E. 33. Fragile X syndrome results from a misfolded neuroprotein. RNase P and 28S rRNA both:
A. Act as RNA polymerases. B. Catalyse the formation of peptide bonds. C. Contain RNA which has catalytic activity. D. Have ribonuclease activity. E. Have reverse transcriptase activity. 9128A Drug Discovery and Design A – June 2009 34. As a check on the scanning procedure record an answer of A to question 34. 35. High levels of telomerase activity are typically found in: 36. 37. A. Normal somatic cells during rapid proliferation. B. Bacterial cells during transcription. C. Terminally differentiated somatic cells. D. Immortal cell lines. E. Cells infected with a virus. Page 11 of 32 pages Exposure of DNA to UV light is most likely to result in:
A. the cleavage of backbone phosphodiester bonds B. the formation of covalent bonds between two adjacent pyrimidines C. de-purination by cleavage of N-glycosidic bonds D. the conversion of adenine to its alternative tautomer E. the conversion of cytosine to uracil A researcher engineers a colony of E. coli by removing the trp promoter (including the
operator) from the trp operon and replacing it with the lac promoter also including the
operator. This would have the effect of:
A. Producing lots of lactose when the cells are fed tryptophan B. Producing lots of β-galactosidase with low tryptophan C. Preventing β-galactosidase synthesis only when tryptophan was high D. Producing lots of tryptophan when [lactose] was high. E. Degrading lots of tryptophan when the [lactose] is high 9128A Drug Discovery and Design A – June 2009 Page 12 of 32 pages Questions 38 to 40 refer to the table below
You have isolated a number of mutations in E. coli in the lac operon. The normal (wild type) βgalactosidase protein has a molecular weight of 115 kD. The following information has been
provided for each colony. The term “altered” refers to a change from the wild type sequence. The
molecular weight of the β-galactosidase produced by each colony was measured using SDS-PAGE.
The DNA sequence of lacZ and the amino acid sequence of the gene product, β-galactosidase, were
determined and compared to the wild type sequence. lacZ gene sequence
β-galactosidase
molecular weight (kD)
Amino acid sequence
Activity (% wild type) A
altered B
altered Colony
C
altered 115 5 115 0 115 unaltered
100 altered
0 altered
100 N/A
0 altered
10 D
unaltered E
altered 38. Which of the following colonies (A, B, C, D or E) is most likely to result from a frameshift
mutation in lacZ? 39. Which of the following colonies (A, B, C, D, or E) displays a mutation which can be
explained by the degeneracy of the genetic code? 40. Which of the following colonies (A, B, C, D, or E) is most likely to result from a mutation
which disrupts the promoter region? 41. You have set up a number of plates to test a compound’s mutagenicity using the Ames test.
The figure below shows schematic diagrams of 5 plates. Which plate (A, B, C, D,or E)
represents the growth pattern if the medium in the plate contained physiological
concentrations of histidine? Plate A Plate B Disc to which
compound can
be applied Plate C Plate D Plate E 9128A Drug Discovery and Design A – June 2009 Page 13 of 32 pages 4 2 . Which statement about eukaryotic RNA polymerases is INCORRECT? A. RNA Polymerase I transcripts are translated very efficiently B. RNA Polymerase II promoters often contain a TATA element C. RNA polymerase II transcripts are the most diverse D. RNA Polymerase II is the most sensitive to alpha amanitin E. RNA Polymerase III promoter elements are mostly within the transcribed
sequence 43. 44. Normally the eukaryotic C-terminal domain (CTD) RNA polymerase II: A. adds a ‘cap’ to the 5’ end of mRNA B. forms part of the spliceosome C. catalyses polyadenylation at the 3' end of mRNA D. can be phosphorylated by a transcription factor E. cleaves mRNA in preparation for splicing PEPCK is up-regulated during starvation. Which of the following statements about this
regulation is INCORRECT? During starvation…. A. glucagon binds to cell surface receptors and activates adenylyl cyclase B. increased cAMP results in increased stability of PEPCK mRNA C. activated Protein Kinase A phosphorylates a transcription factor, CREB D. PEPCK is allosterically activated by cAMP E. glucocorticoids bind to intracellular receptors and activate the transcription of
PEPCK 9128A Drug Discovery and Design A – June 2009 Page 14 of 32 pages The diagram below is used for the following 1 question (Question 45). The vertical axis is relative
biological activity. The curves are labelled X,Y and Z, but they may represent different situations
in each question. 45. 46. If curves X,Y and Z represent the dose-response curve for agonist X, Y and Z respectively,
the compound Z: A. has an intrinsic activity the same as X. B. has a potency half that of agonists X and Y. C. has a lower intrinsic activity than 1.0 as Z is a partial agonist. D. answers B and C are correct. E. answers A and B are correct. An inverse agonist is a ligand that: A. is an antagonist. B. requires an allosteric model of drug action to explain its activity. C. produces a response lower than basal. D. Answers A and C are correct. E. Answers B and C are correct. 9128A 47. Drug Discovery and Design A – June 2009 Page 15 of 32 pages The specificity of a drug for its receptor is the:
A. ability of an agonist to produce its maximum response compared to a standard. B. production of drug effects by interaction with only a single receptor. C. ability of an agonist to produce the response of a standard agonist. D. negative log dose of a drug at which the receptor is half maximally occupied. E. production of a particular drug effect at lower doses than those producing multiple
effects. 48. The occupancy theory (Clark) of receptor theory of drug action: A. states that the effects are not directly proportional to the proportion of receptors
occupied B. assumes that full response is not possible from a full agonist at low receptor
occupancies. C. assumes that a maximal response occurs when all the available receptors are
occupied. 49. D. A and C are correct E. B and C are correct Gs
A. causes the release of calcium ions B. inhibits adenylyl cyclase C. activates adenylyl cyclase D. inhibits phospholipase C-β E. activates phospholipase C-β 9128A 50. Drug Discovery and Design A – June 2009 Page 16 of 32 pages Which of the following statements are CORRECT? Enzyme-linked receptors
A. are transmembrane proteins with their ligand-binding domain on the outer surface
of the plasma membrane B. are characterised as having a cytosolic domain that either has an intrinsic enzyme
activity or associates directly with an enzyme C. include receptor tyrosine kinases D. includes the receptors for epidermal growth factor and vascular endothelial
growth factor E. 51. All of the above Which of the following statements are CORRECT? A. GTPase-activating proteins (GAPs) maintain most of the Ras protein (~ 95%) in
unstimulated cells in an inactive GDP-bound state B. Ras inhibits the MAP-kinase serine/threonine phosphorylation pathway C. GTPase-activating proteins (GAPs) activate Ras by stimulating it to hydrolyze
bound GDP D. Guanine nucleotide exchange factors (GEFs) inhibit Ras E. Ras is inactive when GTP is bound and active when GDP is bound 9128A Drug Discovery and Design A – June 2009 Page 17 of 32 pages THEORY OF PRACTICAL Questions 52 to 57 refer to the following information.
You have been given a mixture of 5 proteins (A - E) to separate and identify. You have been told
that some of these proteins are coloured, containing a heme prosthetic group, which absorbs
strongly at 410 nm. Two of the proteins contain 2 identical subunits (equal molecular weight). You
have carried out the following experiments:
Experiment 1.
Elution Profile: DEAE cellulose pH 7.0 An aliquot of the mixture cellulose at pH 7.0. One mL fractions
were collected and the absorbance
measured at 410 nm and 280 nm. The
first peak eluted contained A and B. A Absorbance (A - E) was loaded onto DEAE 1.8
1.6
1.4
1.2
1.0
0.8
0.6
0.4
0.2
0.0 A 410 nm
0.5 M
NaCl Peak 1 0 second peak, eluted after the addition of A 280 nm Peak 2 5 10 15 20 Volum e (m l) 0.5 M NaCl at pH 7.0 contained two
proteins, C, D and E.
15 µL used in
Experiment 2
Experiment 2. A 15 µl sample of Peak 1 from experiment 1 (proteins A&B) was loaded onto a 1.5 % agarose gel,
made up in Tris barbitol buffer, pH 8.8. The sample was subjected to electrophoresis at 60 V for 45
min and the gel was then stained with Coomassie blue for 40 min. Destaining followed until the
background was clear. The resultant destained gel is shown below. Cathode
-ve Anode
+ve
well A 25 9128A Drug Discovery and Design A – June 2009 Page 18 of 32 pages Experiment 3.
Another aliquot of the protein mixture Elution profile: DEAE cellulose pH 5.0 (A-E) was loaded onto DEAE cellulose in experiment 1. The first peak eluted
contained three proteins A, B and D.
The second peak, C and E, was eluted
after increasing the ionic strength of Absorbance at pH 5.0 using the same procedure as 1.0
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0.0 the buffer. A 280 nm
A 410 nm
0.5 M
NaCl 0 5 10 15 20 25 Volum e (m l) Experiment 4.
Elution profile: G-50 Sephadex
3.0 (A-E) was loaded onto a G-50 Sephadex 2.5 column (cut-off >50 000) equilibrated
with 50 mM Tris pH 7.5. One mL
fractions were collected after measuring
a 30 ml void volume. Two protein peaks
were eluted. The first peak contained Absorbance Another aliquot of the protein mixture A280
A410 2.0
1.5
1.0
0.5
0.0
0 5 10 15 20 Volum e (m l) one protein, A. Experiment 5.
The original protein mixture was loaded onto an SDS-PAGE at pH 8.8. Three protein bands were
observed after Coomassie blue staining:
15 000, 30 000 and 45 000. 25 9128A 52. 53. 54. Drug Discovery and Design A – June 2009 Page 19 of 32 pages What is the most likely molecular weight of protein A? A. 15 000 B. 30 000 C. 45 000 D. 70 000 E. 90 000 What is the pI of protein A? A. 10.5 B. 9.5 C. 8.4 D. 6.5 E. 4 One of the proteins in your mixture (A - E) is a histone H2A. Which protein (A - E) is
Histone H2A? A. Protein A B. Protein B C. Protein C D. Protein D E. Protein E 9128A 55. 56. 57. Drug Discovery and Design A – June 2009 Page 20 of 32 pages If you loaded the original protein mixture (A-E) onto an ion exchange column containing
carboxymethyl cellulose (-ve) at pH 5.0 which proteins would you predict would be eluted
BEFORE the NaCl wash?
A. All the proteins B. None of the proteins C. Proteins A, B & D D. Protein C and E E. Protein A and B Which protein (A – E) would have the highest ratio of basic residues (lysine & arginine)
relative to acidic residues (glutamate & aspartate)?
A. Protein A B. Protein B C. Protein C D. Protein D E. Protein E Your mixture contains ovalbumin. This protein is colourless with a pI of 4.7 and a molecular
weight of 45 000. Which protein (A – E) is ovalbumin?
A. Protein A B. Protein B C. Protein C D. Protein D E. Protein E 9128A Drug Discovery and Design A – June 2009 Page 21 of 32 pages Questions 58 to 62 refer to the following inform...

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