In-situ forming PLG drug delivery was an approach invented by Southern Research Institute scientists. The concept involves administering a PLG polymer solution containing the drug substance such as the antibiotic doxycycline. The resulting liquid formulation is placed into a diseased periodontal pocket. Once in the pocket, the formulation solidifies due to solvent extraction, taking on the shape of the pocket and releasing antibiotic into the pocket for seven days (13). The key with this approach is that the formulation stays in the pocket during antibiotic treatment, especially as the pocket heals and decreases in size. The technology was licensed to Vipont Research Laboratories, which later became Atrix Laboratories. In 1999, Atrix successfully launched a periodontitis product branded as Atridox. Atrix also applied this in-situ forming technology to systemic delivery, for example in its Eligard product (leuprolide acetate injectable suspension) for the extended release of LHRH to treat prostate cancer (14).

Cui, W. et al. Increasing cGMP-dependent protein kinase activity attenuates unilateral ureteral obstruction-induced renal fibrosis. American journal of physiology Renal physiology. 306, F996–1007 (2014).

Hi Alan I can respect that. I have a philosophy degree so my thoughts go all over the place, but I must admit that fear of death motivates many of my musings.

        Moreover, principal investigators for our clinical trials may serve as scientific advisors or consultants to us from time to time and receive compensation in connection with such services. Under certain circumstances, we may be required to report some of these relationships to the FDA or other regulatory authority. The FDA or other regulatory authority may conclude that a financial relationship between us and a principal investigator has created a conflict of interest or otherwise affected interpretation of the study. The FDA or other regulatory authority may therefore question the integrity of the data generated at the applicable clinical trial site and the utility of the clinical trial itself may be jeopardized. This could result in a delay in approval, or rejection, of our marketing applications by the FDA or other regulatory authority, as the case may be, and may ultimately lead to the denial of marketing approval of one or more of our product candidates.

        Given the amount of time required for the development, testing and regulatory review of new product candidates, patents protecting such candidates might expire before or shortly after such candidates are commercialized. We expect to seek extensions of patent terms in the U.S. and, if available, in other countries where we are prosecuting patents. In the U.S., the Drug Price Competition and Patent Term Restoration Act of 1984 permits a patent term extension of up to five years beyond the normal expiration of the patent, which is limited to the approved indication (or any additional indications approved during the period of extension). However, the applicable authorities, including the FDA and the USPTO in the U.S., and any equivalent regulatory authority in other countries, may not agree with our assessment of whether such extensions are available, and may refuse to grant extensions to our patents, or may grant more limited extensions than we request. If this occurs, our competitors may be able to take advantage of our investment in development and clinical trials by referencing our clinical and pre-clinical data and launch their product earlier than might otherwise be the case.

        As of December 31, 2018, we did not have any significant off-balance sheet arrangements, as defined in Item 303(a)(4)(ii) of SEC Regulation S-K promulgated under the Exchange Act.

(a) After oral administration with β-BA (100 mg/kg/d or 200 mg/kg/d) for 7 times. Representative immunohistochemistry staining for p-eNOS (Ser1177) was shown on carotid arotas (bar: 100 μm); (b) HEUVCs were pretreated with β-BA for 24 h before being subjected to 6 h OGD then incubated with β-BA for an additional 24 h. Cells were immunostained with anti-phospho eNOS (Ser1177) antibodies, representative immunofluorescent staining for p-eNOS (Ser1177) was shown (bar 20 μm). DAPI: nuclear staining and merged images were also exhibited. Comparison of fluorescence intensity changes in HUVECs are presented by the histogram. (c) Western blot analysis showed the expression of p-eNOS (Ser1177) in HUVECs, and the blots were operated under the same experimental conditions. The data represent the results (Mean ± SD) of triplicate independent experiments.

(b)      Any fraud, whether or not material, that involves management or other employees who have a significant role in the Company’s internal control over financial reporting.

Tousoulis, D., Kampoli, A. M., Tentolouris, C., Papageorgiou, N. & Stefanadis, C. The role of nitric oxide on endothelial function. Curr Vasc Pharmacol. 10, 4–18 (2012).

Pursuant to the Companies Law and regulations promulgated thereunder with respect to the convening of general meetings in a public company, shareholder meetings generally require prior notice of not less than 21 days, and for certain matters specified in the Companies Law, not less than 35 days. The function of the annual general meeting is to elect directors in accordance with the Articles, receive and consider the profit and loss account, the balance sheet and the ordinary reports and accounts of the directors and auditors, appoint auditors and fix their remuneration and transact any other business which under the Articles or applicable law may be transacted by the shareholders of a company in general meeting.

        The performance graph in this Item 5 shall not be deemed "soliciting material" or be deemed "filed" for purposes of Section 18 of the Exchange Act, or otherwise subject to the liabilities under that Section, and shall not be deemed to be incorporated by reference into any of our filings under the Securities Act, whether made before or after the date hereof and irrespective of any general incorporation language in any such filing.

cADPR levels were measured with a previously described cycling method40. Increases in resorufin fluorescence were measured at 544 nm excitation/590 nm emission wavelengths using a SpectraMax Gemini fluorescence plate reader (Molecular Devices Corp.).