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Notes i ; These options have been granted over shares in Shire Holdings Limited, a previous holding company of the Group. Exercise of these options results in the optionholder receiving ordinary shares in the Company. ii ; Options granted under the Executive Scheme are subject to performance criteria and cannot be exercised in full, unless the Company's share price increases at a compound rate of at least 20.5% per annum over a minimum three-year measurement period. If the Company's share price increases at a compound rate of 14.5% per annum over a minimum three-year measurement period, 60% of the options may be exercised. If these conditions are not met after the initial three years, they are thereafter tested quarterly by reference to share price growth over the extended period. If the share price does not meet these conditions at any time, none of the options will become exercisable. iii ; Options granted under the Sharesave Scheme are granted with an exercise price equal to 80% of the mid-market price on the day before invitations are issued to employees. Following changes in the Inland Revenue rules governing such schemes, employees may now enter into three or five-year savings contracts. iv ; These options have been granted over shares in SLI, formerly Pharmavene Inc., a company acquired by the Group on 23 March 1997. Exercise of these options results in the optionholder receiving ordinary shares in the Company. As a result of the acquisition of SLI, and in accordance with the terms of the original share option plan, all options granted under that plan became immediately capable of exercise. v ; These options have been granted over shares in SRI, formerly Richwood Pharmaceutical Company, Inc., a company acquired by the Group on 22 August 1997. Exercise of these options results in the optionholder receiving ordinary shares in the Company. As a result of the acquisition of SRI, and in accordance with the terms of the original share option plan, all options granted under that plan became immediately capable of exercise. vi ; These options have been granted over shares in Roberts Pharmaceutical Corporation, a company acquired by the Group on 23 December 1999. Exercise of these options results in the optionholder receiving ordinary shares in the Company. As a result of the acquisition of Roberts, and in accordance with the terms of the original Roberts share option plan, all options granted under that plan became immediately capable of performance. vii ; Options granted under the 2000 Executive Scheme are subject to criteria and cannot be exercised in full, unless the Company's share price increases at a compound rate of at least 20.5% per annum over a minimum three-year period. If the Company's share price increases at a compound rate of at least 14.5% per annum over a minimum three-year measurement period, 60% of the options will be exercisable. If these conditions are not met after the initial three-year measurement period, they will thereafter be tested quarterly by reference to compound annual share price growth over an extended period. If the share price does not meet these conditions at any time, none of these options will become exercisable. At the Annual General Meeting of the Company held on 5 June 2001, a resolution was passed to permit the grant of options under the 2000 Executive Scheme to be made subject to performance criteria determined prior to the date of grant. Subsequent to the passing of this resolution options have been granted based on a performance criteria being satisfied before grant namely that the Company's share price had increased by an annualised compound rate of 20.5% over a minimum three-year period. viii ; Following the merger with BioChem Pharma Inc. on 11 May 2001, the BioChem Stock Option Plan was amended such that options over BioChem's common stock became options over ordinary shares of the Company. All BioChem options, which were not already exercisable, vested and became exercisable as a result of the merger. It is intended that no further options will be granted under the BioChem Stock Option Plan. ix ; Under the Stock Purchase Plan options are granted with an exercise price equal to 85% of the fair market value of a share on the enrolment date the first day of the offering period ; or the exercise date the last day of the offering period ; , whichever is lower. The offering period is for 27 months and lioresal.
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Newly Hired Employee: Coverage for newly eligible Participants is effective the first of the month following the date of employment. Employees hired on the first working day of the month have coverage beginning that day. Election to participate in the health benefits program must be made within 31 days from the date of hire. Open Enrollment: This is an annual period when the program allows employees to enroll and or make benefit and membership changes to their health benefits plan. The annual open enrollment for most The Local Choice Groups is held between April 1 and May 15. However, school groups with an October 1 renewal date may hold the annual open enrollment between August 15 and September 15. Qualifying Status Change: Membership changes due to a qualifying status change must be made within 31 days of the change. Moving out of Your Plan's Service Area: You may change to another plan but You may not change Your membership status ; if You move out of Your plan's service area. Termination of Coverage: Coverage terminates the last day of the month in which a Participant loses eligibility and benazepril.
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Cells, the maximal level being 4.05 pmol 106 cells, which is 2.8-fold higher than that accumulated by PGEz in untransfected cells. On the other hand, PGE2 neither inhibited forskolin-induced cAMP formation andnor accumulated inositol phosphates data notshown ; . These results demonstratethat this receptor is an EP2subtype coupled exclusively to stimulation of adenylate cyclase. Since it wouldbe difficult to examine the signal transduction of EP2 receptor in detail in transiently transfected cells, stable expression of the cloned EPz receptor in Chinese hamster ovary cells is now in progress in our laboratory. Fig. 4 shows the comparison of the amino acid sequences of the mouse EP3 15 ; and thromboxane TX ; Az receptors 28 ; . The sequence of the mouse EP2 receptor is 36.2% identical to that the mouse EP3 receptor within the hydrophobic of segments. The identity is 29.9% between the mouse EPz and TXAz receptors within the hydrophobic segments of the two. The most highly conserved region among these three receptors is segment VII. Within the segment VII, Arg-344 in the EP2 is equivalent to Arg-309 in the EP3 and Arg-295 in the TXAz receptor. Considering that retinal is attached to Lys-296 of bovine rhodopsin in segment VI1 29 ; , the structuralfeatures of segment VI1 including Arg residue may reflect the acidic nature of the ligand for the prostanoid receptors. Similar to the &adrenergic receptor 30 ; , EPz receptor has the four potential phosphorylation sites by CAMP-dependent protein kinase 31 ; in the third intracellular loop and carboxyl-terminal tail, andhas many serine and threonineresidues at the COOH-terminal tail as potentialreceptor kinase phosphorylation sites. These phosphorylation sites may be involved in CAMP-mediated heterologous and agonist-induced homologous desensitization, respectively 32 ; . Fig. 5 shows the Northern blot analysis of various organs. A positive band is observed at 3.9 kilobases in most of tissues, suggesting widespread distribution of the EP2 receptor. The tissues highly expressing EP2 mRNA were ileum and thymus, in which PGEz induces relaxation of ileum circular muscle 8 ; and inhibits proliferation of T cells by increasing intracellular cAMP levels 13 ; . A significant band was also observed in lung, spleen, heart, and uterus. is known that PGE2has the It relaxant activity in trachea 7 ; and myometrium 33 ; . On the other hand, EP2 mRNA was not detectable in testis and liver. In summary, we present here the complete amino acid sequence of the mouse EP2 subtype PGE receptor and provide direct proof that this receptor functionally couples to adenylate cyclase in astimulatorymanner. This workwillbe useful for molecular studies on function of the EP2 receptor and for understanding diverse physiological roles of PGEz through PGE receptor subtypes and urecholine and brethine, for instance, pregnancy.
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