Programs time out trying to open- Server Slow- Logon Slow

I am out of ideas on what is going on---

Servers-- 2 Dell R710 one has 96 GB ram the other 128, ESXI 4.2, 3 data stores each 2 SSD & 1 SATA, 4 NIC cards, 16 logical proc.

Box 1 has - 10 virts 2 of them TS - server 03
Box 2 has - 7 virts 4 of them TS 3 server o3 & 1 server 08
each TS has 8 gb memory allocated to it and 4 cpu
split network across the NIC's so no more than 2 TS to 1 NIC  all connected to GB ports

here is the issue-
about a week ago i started having really crappy performance, some applications werent opening, other timed out. To logon took over 5 minutes. I have looked at everything i can think of-
1. ran dns diag on DC-- ok
2. cleared dns and temp on TS
3. watched memory, cpu, and disk on TS-- normal
4. watched network traffic on switch-- ok
5. process explorer -- nothing abnormal
6. 100 other things.

the one program is a custom VB program that connects to our erp database.
another is a maintenacne program that connects to sql -- Different servers
but all in all it is just running so slow. i thought maybe my hard drives were going bad but different hosts and different data stores.
The problem does not seem to be consistant either. one minute the programs work ok on one server then they start crapping out, same with the others.
I have checked the event logs -- have some errors about gp and start menu but that is about it.
The VB application is installed local on TS - have a logon script that puts and icon on the desktop that points to shared folder on file server- its a click once app.
i have done all the usual --reboots, reg scans, clearing temp files, etc.
There is not av on the TS

Any thoughts on where to go next??